Cytokine inhibitors

ABSTRACT

Disclosed are compounds of formula (I) 
                         
Where Ar 1 , X, Y, Q, W, R 3 , R 4 , R 5 , R 6  and R y  are defined herein. The compounds of the invention inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease. The compounds are also useful for treating diseases or conditions related to oncology and anticoagulant or fibrinolytic therapy. Also disclosed are processes for preparing these compounds and pharmaceutical compositions comprising these compounds.

APPLICATION DATA

This application claims benefit to U.S. provisional application No.60/453,364 filed Mar. 10, 2003.

BACKGROUND OF THE INVENTION

1. Technical Field

This invention relates to compounds of formula (I)

The compounds of the invention inhibit production of cytokines involvedin inflammatory processes and are thus useful for treating diseases andpathological conditions involving inflammation such as chronicinflammatory disease. This invention also relates to processes forpreparing these compounds and to pharmaceutical compositions comprisingthese compounds.

2. Background Information

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are importantbiological entities collectively referred to as proinflammatorycytokines which play a role in cytokine mediated diseases. These, alongwith several other related molecules, mediate the inflammatory responseassociated with the immunological recognition of infectious agents. Theinflammatory response plays an important role in limiting andcontrolling pathogenic infections. Elevated levels of proinflammatorycytokines are also associated with a number of diseases of autoimmunitysuch as toxic shock syndrome, rheumatoid arthritis, osteoarthritis,diabetes and inflammatory bowel disease (Dinarello, C. A., et al., 1984,Rev. Infect. Disease 6:51). In these diseases, chronic elevation ofinflammation exacerbates or causes much of the pathophysiology observed.For example, rheumatoid synovial tissue becomes invaded withinflammatory cells that result in destruction to cartilage and bone(Koch, A. E., et al., 1995, J. Invest. Med. 43: 28–38). Studies suggestthat inflammatory changes mediated by cytokines may be involved inendothelial cell pathogenesis including restenosis after percutaneoustransluminal coronary angioplasty (PTCA) (Tashiro, H., etal., 2001March, Coron Artery Dis 12(2):107–13). An important and acceptedtherapeutic approach for potential drug intervention in these diseasesis the reduction of proinflammatory cytokines such as TNF (also referredto in its secreted cell-free form as TNFα) and IL-1β. A number ofanti-cytokine therapies are currently in clinical trials. Efficacy hasbeen demonstrated with a monoclonal antibody directed against TNFα in anumber of autoimmune diseases (Heath, P., “CDP571: An Engineered HumanIgG4 Anti-TNFα Antibody” IBC Meeting on Cytokine Antagonists,Philadelphia, Pa., Apr. 24–5, 1997). These include the treatment ofrheumatoid arthritis, Crohn's disease and ulcerative colitis (Rankin, E.C. C., et al., 1997, British J. Rheum. 35: 334–342 and Stack, W. A., etal., 1997, Lancet 349: 521–524). The monoclonal antibody is thought tofunction by binding to both soluble TNFα and to membrane bound TNF.

A soluble TNFα receptor has been engineered that interacts with TNFα.The approach is similar to that described above for the monoclonalantibodies directed against TNFα; both agents bind to soluble TNFα, thusreducing its concentration. One version of this construct, called Enbrel(Immunex, Seattle, Wash.) recently demonstrated efficacy in a Phase IIIclinical trial for the treatment of rheumatoid arthritis (Brower et al.,1997, Nature Biotechnology 15: 1240). Another version of the TNFαreceptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, N.J.) hasdemonstrated efficacy in various animal models of allergic lunginflammation and acute lung injury. Ro 45-2081 is a recombinant chimericmolecule constructed from the soluble 55 kDa human TNF receptor fused tothe hinge region of the heavy chain IgG1 gene and expressed ineukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S143). IL-1has been implicated as an immunological effector molecule in a largenumber of disease processes. IL-1 receptor antagonist (IL-1ra) had beenexamined in human clinical trials. Efficacy has been demonstrated forthe treatment of rheumatoid arthritis (Antril, Amgen). In a phase IIIhuman clinical trial IL-1ra reduced the mortality rate in patients withseptic shock syndrome (Dinarello, 1995, Nutrution 11, 492).Osteoarthritis is a slow progressive disease characterized bydestruction of the articular cartilage. IL-1 is detected in synovialfluid and in the cartilage matrix of osteoarthritic joints. Antagonistsof IL-1 have been shown to diminish the degradation of cartilage matrixcomponents in a variety of experimental models of arthritis (Chevalier,1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator ofcardiovascular homeostasis, neurotransmission and immune function;recently it has been shown to have important effects in the modulationof bone remodeling. Cytokines such as IL-1 and TNF are potentstimulators of NO production. NO is an important regulatory molecule inbone with effects on cells of the osteoblast and osteoclast lineage(Evans, et al., 1996, J Bone Miner Res. 11, 300). The promotion ofbeta-cell destruction leading to insulin dependent diabetes mellitusshows dependence on IL-1. Some of this damage may be mediated throughother effectors such as prostaglandins and thromboxanes. IL-1 can effectthis process by controlling the level of both cyclooxygenase II andinducible nitric oxide synthetase expression (McDaniel et al., 1996,Proc Soc Exp Biol Med. 211, 24).

Inhibitors of cytokine production are expected to block induciblecyclooxygenase (COX-2) expression. COX-2 expression has been shown to beincreased by cytokines and it is believed to be the isoform ofcyclooxygenase responsible for inflammation (M. K. O'Banion et al.,Proc. Natl. Acad. Sci. U.S.A, 1992, 89,4888.) Accordingly, inhibitors ofcytokines such as IL-1 would be expected to exhibit efficacy againstthose disorders currently treated with COX inhibitors such as thefamiliar NSAIDs. These disorders include acute and chronic pain as wellas symptoms of inflammation and cardiovascular disease.

Elevation of several cytokines have been demonstrated during activeinflammatory bowel disease (IBD). A mucosal imbalance of intestinal IL-1and IL-1ra is present in patients with IBD. Insufficient production ofendogenous IL-1ra may contribute to the pathogenesis of IBD (Cominelli,et al., 1996, Aliment Pharmacol Ther. 10, 49). Alzheimer disease ischaracterized by the presence of beta-amyloid protein deposits,neurofibrillary tangles and cholinergic dysfunction throughout thehippocampal region. The structural and metabolic damage found inAlzheimer disease is possibly due to a sustained elevation of IL-1(Holden, et al., 1995, Med Hypotheses, 45, 559). A role for IL-1 in thepathogenesis of human immunodeficiency virus (HIV) has been identified.IL-1ra showed a clear relationship to acute inflammatory events as wellas to the different disease stages in the pathophysiology of HIVinfection (Kreuzer, et al., 1997, Clin Exp Immunol. 109, 54). IL-1 andTNF are both involved in periodontal disease. The destructive processassociated with periodontal disease may be due to a disregulation ofboth IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).

Proinflammatory cytokines such as TNFα and IL-1β are also importantmediators of septic shock and associated cardiopulmonary dysfunction,acute respiratory distress syndrome (ARDS) and multiple organ failure.In a study of patients presenting at a hospital with sepsis, acorrelation was found between TNFα and IL-6 levels and septiccomplications (Terregino et al., 2000, Ann. Emerg. Med., 35, 26). TNFαhas also been implicated in cachexia and muscle degradation, associatedwith HIV infection (Lahdiverta et al., 1988, Amer. J. Med., 85, 289).Obesity is associated with an increase incidence of infection, diabetesand cardiovascular disease. Abnormalities in TNFα expression have beennoted for each of the above conditions (Loffreda, et al., 1998, FASEB J.12, 57). It has been proposed that elevated levels of TNFα are involvedin other eating related disorders such as anorexia and bulimia nervosa.Pathophysiological parallels are drawn between anorexia nervosa andcancer cachexia (Holden, et al., 1996, Med Hypotheses 47, 423). Aninhibitor of TNFα production, HU-211, was shown to improve the outcomeof closed brain injury in an experimental model (Shohami, et al., 1997,J. Neuroimmunol. 72, 169). Atherosclerosis is known to have aninflammatory component and cytokines such as IL-1 and TNF have beensuggested to promote the disease. In an animal model an IL-1 receptorantagonist was shown to inhibit fatty streak formation (Elhage et al.,1998, Circulation, 97, 242). TNFα levels are elevated in airways ofpatients with chronic obstructive pulmonary disease and it maycontribute to the pathogenesis of this disease (M. A. Higham et al.,2000, Eur. Respiratory J., 15, 281). Circulating TNFα may alsocontribute to weight loss associated with this disease (N. Takabatake etal., 2000, Amer. J. Resp. & Crit. Care Med., 161 (4 Pt 1), 1179).Elevated TNFα levels have also been found to be associated withcongestive heart failure and the level has been correlated with severityof the disease (A. M. Feldman et al., 2000, J. Amer. College ofCardiology, 35, 537). In addition, TNFα has been implicated inreperfusion injury in lung (Borjesson et al., 2000, Amer. J. Physiol.,278, L3–12), kidney (Lemay et al., 2000, Transplantation, 69, 959), andthe nervous system (Mitsui et al., 1999, Brain Res., 844, 192).

TNFα is also a potent osteoclastogenic agent and is involved in boneresorption and diseases involving bone resorption (Abu-Amer et al.,2000, J. Biol. Chem., 275, 27307). It has also been found highlyexpressed in chondrocytes of patients with traumatic arthritis(Melchiorri et al., 2000, Arthritis and Rheumatism, 41, 2165). TNFα hasalso been shown to play a key role in the development ofglomerulonephritis (Le Hir et al., 1998, Laboratory Investigation, 78,1625).

The abnormal expression of inducible nitric oxide synthetase (iNOS) hasbeen associated with hypertension in the spontaneously hypertensive rat(Chou et al., 1998, Hypertension, 31, 643). IL-1 has a role in theexpression of iNOS and therefore may also have a role in thepathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension,9, 867).

IL-1 has also been shown to induce uveitis in rats which could beinhibited with IL-1 blockers. (Xuan et al., 1998, J. Ocular Pharmacol.and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have beenshown to stimulate proliferation of acute myelogenous leukemia blasts(Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essentialfor the development of both irritant and allergic contact dermatitis.Epicutaneous sensitization can be prevented by the administration of ananti-IL-1 monoclonal antibody before epicutaneous application of anallergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177). Dataobtained from IL-1 knock out mice indicates the critical involvement infever for this cytokine (Kluger et al., 1998, Clin Exp PharmacolPhysiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 andIL-8 initiate the acute-phase reaction which is stereotyped in fever,malaise, myalgia, headaches, cellular hypermetabolism and multipleendocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813).The production of these inflammatory cytokines rapidly follows trauma orpathogenic organism invasion.

Other proinflammatory cytokines have been correlated with a variety ofdisease states. IL-8 correlates with influx of neutrophils into sites ofinflammation or injury. Blocking antibodies against IL-8 havedemonstrated a role for IL-8 in the neutrophil associated tissue injuryin acute inflammation (Harada et al., 1996, Molecular Medicine Today 2,482). Therefore, an inhibitor of IL-8 production may be useful in thetreatment of diseases mediated predominantly by neutrophils such asstroke and myocardial infarction, alone or following thrombolytictherapy, thermal injury, adult respiratory distress syndrome (ARDS),multiple organ injury secondary to trauma, acute glomerulonephritis,dermatoses with acute inflammatory components, acute purulent meningitisor other central nervous system disorders, hemodialysis, leukopherisis,granulocyte transfusion associated syndromes, and necrotizingenterocolitis.

Rhinovirus triggers the production of various proinflammatory cytokines,predominantly IL-8, which results in symptomatic illnesses such as acuterhinitis (Winther et al., 1998, Am J Rhinol. 12, 17).

Other diseases that are effected by IL-8 include myocardial ischemia andreperfusion, inflammatory bowel disease and many others.

The proinflammatory cytokine IL-6 has been implicated with the acutephase response. IL-6 is a growth factor in a number in oncologicaldiseases including multiple myeloma and related plasma cell dyscrasias(Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has alsobeen shown to be an important mediator of inflammation within thecentral nervous system. Elevated levels of IL-6 are found in severalneurological disorders including AIDS dementia complex, Alzheimer'sdisease, multiple sclerosis, systemic lupus erythematosus, CNS traumaand viral and bacterial meningitis (Gruol, et al., 1997, MolecularNeurobiology 15: 307). IL-6 also plays a significant role inosteoporosis. In murine models it has been shown to effect boneresorption and to induce osteoclast activity (Ershler et al., 1997,Development and Comparative Immunol. 21: 487). Marked cytokinedifferences, such as IL-6 levels, exist in vivo between osteoclasts ofnormal bone and bone from patients with Paget's disease (Mills, et al.,1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shownto be involved in cancer cachexia. The severity of key parameters ofcachexia can be reduced by treatment with anti IL-6 antibodies or withIL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins Mol Ther.1, 107). Several infectious diseases, such as influenza, indicate IL-6and IFN alpha as key factors in both symptom formation and in hostdefense (Hayden, et al., 1998, J Clin Invest. 101, 643). Overexpressionof IL-6 has been implicated in the pathology of a number of diseasesincluding multiple myeloma, rheumatoid arthritis, Castleman's disease,psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997,Protein Sci. 6, 929). Compounds that interfered with the production ofcytokines including IL-6, and TNF were effective in blocking a passivecutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem., 41,1050).

GM-CSF is another proinflammatory cytokine with relevance to a number oftherapeutic diseases. It influences not only proliferation anddifferentiation of stem cells but also regulates several other cellsinvolved in acute and chronic inflammation. Treatment with GM-CSF hasbeen attempted in a number of disease states including bum-woundhealing, skin-graft resolution as well as cytostatic and radiotherapyinduced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF alsoappears to play a role in the replication of human immunodeficiencyvirus (HIV) in cells of macrophage lineage with relevance to AIDStherapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41).Bronchial asthma is characterised by an inflammatory process in lungs.Involved cytokines include GM-CSF amongst others (Lee, 1998, J R CollPhysicians Lond 32, 56).

Interferon γ (IFN γ) has been implicated in a number of diseases. It hasbeen associated with increased collagen deposition that is a centralhistopathological feature of graft-versus-host disease (Parkman, 1998,Curr Opin Hematol. 5, 22). Following kidney transplantation, a patientwas diagnosed with acute myelogenous leukemia. Retrospective analysis ofperipheral blood cytokines revealed elevated levels of GM-CSF and IFN γ.These elevated levels coincided with a rise in peripheral blood whitecell count (Burke, et al., 1995, Leuk Lymphoma. 19, 173). Thedevelopment of insulin-dependent diabetes (Type 1) can be correlatedwith the accumulation in pancreatic islet cells of T-cells producing IFNγ (Ablumunits, et al., 1998, J Autoimmun. 11, 73). IFN γ along with TNF,IL-2 and IL-6 lead to the activation of most peripheral T-cells prior tothe development of lesions in the central nervous system for diseasessuch as multiple sclerosis (MS) and AIDS dementia complex (Martino etal., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions result inarterial disease that can lead to cardiac and cerebral infarction. Manyactivated immune cells are present in these lesions, mainly T-cells andmacrophages. These cells produce large amounts of proinflammatorycytokines such as TNF, IL-1 and IFN γ. These cytokines are thought to beinvolved in promoting apoptosis or programmed cell death of thesurrounding vascular smooth muscle cells resulting in theatherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76).Allergic subjects produce mRNA specific for IFN γ following challengewith Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342).The expression of a number of cytokines, including IFN γ has been shownto increase following a delayed type hypersensitivity reaction thusindicating a role for IFN γ in atopic dermatitis (Szepietowski, et al.,1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologicstudies were performed in cases of fatal cerebral malaria. Evidence forelevated IFN γ amongst other cytokines was observed indicating a role inthis disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501).The importance of free radical species in the pathogenesis of variousinfectious diseases has been established. The nitric oxide synthesispathway is activated in response to infection with certain viruses viathe induction of proinflammatory cytokines such as IFN γ (Akaike, etal., 1998, Proc Soc Exp Biol Med. 217, 64). Patients, chronicallyinfected with hepatitis B virus (HBV) can develop cirrhosis andhepatocellular carcinoma. Viral gene expression and replication in HBVtransgenic mice can be suppressed by a post-transcriptional mechanismmediated by IFN γ, TNF and IL-2 (Chisari, et al., 1995, Springer SeminImmunopathol. 17, 261). IFN γ can selectively inhibit cytokine inducedbone resorption. It appears to do this via the intermediacy of nitricoxide (NO) which is an important regulatory molecule in bone remodeling.NO may be involved as a mediator of bone disease for such diseases as:rheumatoid arthritis, tumor associated osteolysis and postmenopausalosteoporosis (Evans, et al., 1996, J Bone Miner Res. 11, 300). Studieswith gene deficient mice have demonstrated that the IL-12 dependentproduction of IFN γ is critical in the control of early parasiticgrowth. Although this process is independent of nitric oxide the controlof chronic infection does appear to be NO dependent (Alexander et al.,1997, Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an importantvasodilator and convincing evidence exists for its role incardiovascular shock (Kilbourn, et al., 1997, Dis Mon. 43, 277). IFN γis required for progression of chronic intestinal inflammation in suchdiseases as Crohn's disease and inflammatory bowel disease (IBD)presumably through the intermediacy of CD4+ lymphocytes probably of theTH1 phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43). Anelevated level of serum IgE is associated with various atopic diseasessuch as bronchial asthma and atopic dermatitis. The level of IFN γ wasnegatively correlated with serum IgE suggesting a role for IFN γ inatopic patients (Teramoto et al., 1998, Clin Exp Allergy 28, 74).

WO 01/01986 discloses particular compounds alleged to having the abilityto inhibit TNF-alpha. Certain compounds disclosed in WO 01/01986 areindicated to be effective in treating the following diseases: dementiaassociated with HIV infection, glaucoma, optic-neuropathy, opticneuritis, retinal ischemia, laser induced optic damage, surgery ortrauma-induced proliferative vitreoretinopathy, cerebral ischemia,hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbonmonoxide or manganese or cyanide poisoning, Huntington's disease,Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosisand other demyelinating diseases, amyotrophic lateral sclerosis, headand spinal cord trauma, seizures, convulsions, olivopontocerebellaratrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-relatedneuropathy, MERRF and MELAS syndromes, Leber's disease, Wernicke'sencephalophathy, Rett syndrome, homocysteinuria, hyperprolinemia,hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyricaminoaciduria, sulfite oxidase deficiency, combined systems disease,lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drugaddiction, drug tolerance, drug dependency, depression, anxiety andschizophrenia. WO 02/32862 discloses that inhibitors of pro-inflammatorycytokines including TNFα are allegedly useful for treating acute andchronic inflammation in the lung caused by inhalation of smoke such ascigarette smoke. TNFα anatagonists are apparently also useful for thetreatment of endometriosis, see EP 1022027 A1. Infliximab, in clinicaltrials for RA, has also been indicated to be useful for treating variousinflammatory diseases including Behcet's disease, uveitis and ankylosingspondylitis. Pancreatitis may also be regulated by inflammatory mediatorproduction, see J Surg Res 2000 May 15 90(2)95–101; Shock 1998September. 10(3):160–75. p38MAP kinase pathway plays an role in B.burgdorferi-elicited infammation and may be useful in treatinginflammation induced by the Lyme disease agent. Anguita, J. et. al., TheJournal of Immunology, 2002,168:6352–6357.

Compounds which modulate release of one or more of the aforementionedinflammatory cytokines can be useful in treating diseases associatedwith release of these cytokines. For example, WO 98/52558 disclosesheteroaryl urea compounds which are indicated to be useful in treatingcytokine mediated diseases. WO 99/23091 discloses another class of ureacompounds which are useful as anti-inflammatory agents. WO 99/32463relates to aryl ureas amd their use in treating cytokine diseases andproteolytic enzyme mediated disease. WO 00/41698 discloses aryl ureassaid to be useful in treating p38 MAP kinase diseases.

Compounds active against p38 MAP kinase can also be useful for treatingvarious types of cancers as described in WO 03/068223.

U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N′-heterocyclicsubstituted urea compounds which are described as being useful fortreating hypercholesterolemia and atheroclerosis. Di-substituted aryland heteroaryl compounds are also disclosed in U.S. Pat. Nos. 6,080,763;6,319,921; 6,297,381 and 6,358,945. The compounds in the patents arealleged to possess anti-cytokine activity and are therefore useful intreating diseases associated with inflammation.

The work cited above supports the principle that inhibition of cytokineproduction will be beneficial in the treatment of cytokine mediateddiseases. Therefore a need exists for small molecule inhibitors fortreating these diseases with optimized efficacy, pharmacokinetic andsafety profiles.

BRIEF SUMMARY OF THE INVENTION

The work cited above supports the principle that inhibition of cytokineproduction with small molecule compounds will be beneficial in thetreatment of various disease states.

It is therefore an object of the invention to provide compounds offormula (I)

It is a further object of the invention to provide methods for treatingcytokine mediated diseases and pathological conditions involvinginflammation such as chronic inflammatory disease, using the novelcompounds of the invention.

It is yet a further object of the invention to provide pharmaceuticalcompositions and processes of preparation of the above-mentioned novelcompounds.

DETAILED DESCRIPTION OF THE INVENTION

In the broadest generic embodiment, there is provided compounds of theformula (I)

wherein:

-   Ar¹ is an aromatic carbocycle substituted with one R¹, and wherein    Ar¹ is independently substituted with two R² groups and wherein one    R¹ and one R² on adjacent ring atoms optionally form a 5- or    6-membered carbocyclic or heterocyclic ring;-   R¹ is halogen, NO₂, NH₂, J-N(R^(a))—(CH₂)_(m)—, N(J)₂-(CH₂)_(m)—,    NH₂C(O)—, J-N(R^(a))—C(O)—, J-S(O)_(m)—N(R^(a))—,    J-N(R^(a))—S(O)_(m)— or heterocycle-(CH₂)_(m)— wherein the    heterocyclic group is optionally substituted by C₁₋₅ alkyl;-   Q is a N or CR^(p);-   Y is >CR^(p)R^(v), —CR^(p)═C(R^(v))—, —O—, —N(R^(x))— or >S(O)_(m);    wherein R^(a), R^(p), R^(v), R^(x) and R^(y) are each independently    hydrogen or C₁₋₅ alkyl;-   X is —CH₂—, —N(R^(a))—, —O— or —S—;-   W is N or CH;-   each m is independently 0, 1 or 2;-   J is chosen from C1–10 alkyl and carbocycle each optionally    substituted by R^(b);-   R² is chosen from C1–6 alkyl, C3–7 cycloalkyl optionally substituted    by C1–5 alkyl, C1–4 acyl, aroyl, C1–4 alkoxy, each being optionally    partially or fully halogenated, halogen, C1–6 alkoxycarbonyl,    carbocyclesulfonyl and —SO₂—CF₃;-   each R³, R⁴ and R⁵ are independently chosen from hydrogen, C1–6    alkyl and halogen;-   R⁶ is optionally attached at a position ortho or meta to the N atom    of the indicated ring, and is chosen from-   a bond, —O—, —O—(CH₂)₁₋₅—, >C(O), —NH—, —C(O)—NH—, —S—, C₁₋₅ alkyl    branched or unbranched, C₂₋₅ alkenyl, C₁₋₃ acyl, C₁₋₃ alkyl(OH),    heterocycle selected from morpholinyl, piperazinyl, piperidinyl,    pyrrolidinyl and tetrahydrofuranyl, heteroaryl selected from    pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,    imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, thiazolyl,    oxazolyl and isothiazolyl or aryl each alkyl, alkenyl, acyl,    heterocycle, heteroaryl and aryl are optionally substituted by one    to three hydroxy, oxo, C₁₋₃ alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl,    —NR₇R₈ or NR₇R₈—C(O)—;    wherein each R₆ is further optionally covalently attached to groups    chosen from:    -   hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl, hydroxy,        C₁₋₃ alkoxy, phenoxy, benzyloxy, arylC₀₋₄ alkyl, heteroaryl C₀₋₄        alkyl and heterocycle C₀₋₄alkyl, each above-listed heterocycle,        heteroaryl and aryl group is optionally substituted by one to        three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅        alkoxycarbonyl, NR₇R₈—C(O)— or C₁₋₄ acyl;-   each R₇ and R₈ are independently hydrogen, phenylC₀₋₃alkyl    optionally subtituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino,    or R₇ and R₈ are C₁₋₂ acyl, benzoyl or C₁₋₅ branched or unbranched    alkyl optionally substituted by C₁₋₄ alkoxy, hydroxy or mono or    diC₁₋₃ alkyl amino;    and-   R^(b) is chosen from hydrogen, C1–5 alkyl, hydroxyC1–5 alkyl, C2–5    alkenyl, C2–5 alkynyl, carbocycle, heterocycle, heteroaryl, C1–5    alkoxy, C1–5 alkylthio, amino, C1–5 alkylamino, C1–5 dialkylamino,    C1–5 acyl, C1–5 alkoxycarbonyl, C1–5 acyloxy, C1–5 acylamino, each    of the aforementioned are optionally partially or fully halogenated,    or-   R^(b) is chosen from C1–5 alkylsulphonylamino, hydroxy, oxo,    halogen, nitro and nitrile;    or the pharmaceutically acceptable salts, acids, esters or isomers    thereof.

In another embodiment, there are provided compounds of the formula (I)as described above and wherein

-   Y is —O—, —S—, —NH—, —N(CH₂CH₃)— or —N(CH₃)—;-   X is —N(R^(a))—, or —O—;-   Q is CH;-   J is chosen from C1–10 alkyl, aryl or C3–7 cycloalkyl each    optionally substituted by R^(b);-   R₂ is independently chosen from C1–6 alkyl, C3–6 cycloalkyl    optionally substituted by C1–3 alkyl, acetyl, aroyl, C1–5 alkoxy,    each being optionally partially or fully halogenated, halogen,    methoxycarbonyl, phenylsulfonyl and —SO₂—CF₃;-   each R³, R⁴ and R⁵ are hydrogen;-   R^(b) is chosen from hydrogen, C1–5 alkyl, C2–5 alkenyl, C2–5    alkynyl, C3–8 cycloalkylC0–2 alkyl, aryl, C1–5 alkoxy, C1–5    alkylthio, amino, C1–5 alkylamino, C1–5 dialkylamino, C1–5 acyl,    C1–5 alkoxycarbonyl, C1–5 acyloxy, C1–5 acylamino, C1–5    sulphonylamino, hydroxy, halogen, trifluoromethyl, nitro, nitrile or    R^(b) is chosen from; heterocycle chosen from pyrrolidinyl,    pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,    thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl,    tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl,    1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl,    tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene    sulfoxide, pentamethylene sulfone, tetramethylene sulfide,    tetramethylene sulfoxide and tetramethylene sulfone and heteroaryl    chosen from aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl,    thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl,    imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl,    quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,    benzothienyl, quinolinyl, quinazolinyl, naphthyridinyl, indazolyl,    triazolyl, pyrazolo[3,4-b]pyrimidinyl, purinyl,    pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl, tubercidinyl,    oxazo[4,5-b]pyridinyl and imidazo[4,5-b]pyridinyl.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   Ar¹ is chosen from phenyl, naphthyl, tetrahydronaphthyl, indanyl and    indenyl, each Ar¹ is optionally substituted with one R¹, and    independently substituted with two R² groups;-   Y is —O—, —S— or —N(CH₃)—;-   R⁶ is present, and is chosen from-   a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkyl branched or    unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), heterocycle selected from    morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl and    tetrahydrofuranyl, or aryl chosen from phenyl and naphthyl, each    alkyl, alkenyl, heterocycle and aryl are optionally substituted by    one to three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl    amino, amino or C₁₋₅ alkoxycarbonyl;    wherein each R₆ is further optionally covalently attached to groups    chosen from:    -   hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl, hydroxy,        C₁₋₃ alkoxy, phenoxy, benzyloxy, phenylC₀₋₄ alkyl,        piperazinylC₀₋₄ alkyl, piperidinyl C₀₋₄alkyl, pyrrolidinylC₀₋₄        alkyl, morpholinylC₀₋₄ alkyl, tetrahydrofuranylC₀₋₄ alkyl,        triazolyl C₀₋₄alkyl, imidazolyl C₀₋₄alkyl and pyridinyl        C₀₋₄alkyl, each abovelisted heterocycle, heteroaryl and phenyl        group is optionally substituted by one to three hydroxy, oxo,        C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl, —NR₇R₈,        NR₇R₈—C(O)— or C₁₋₄ acyl;-   each R₇ and R₈ are independently hydrogen, phenylC₀₋₃alkyl    optionally subtituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino,    or R₇ and R₈ are C₁₋₂ acyl, benzoyl or C₁₋₅ branched or unbranched    alkyl optionally substituted by C₁₋₄ alkoxy, hydroxy or mono or    diC₁₋₃ alkyl amino.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   X is —O—;-   Y is —N(CH₃)—;-   J is C1–10 alkyl optionally substituted by R^(b);-   R₂ is independently chosen from C1–6 alkyl, C3–6 cycloalkyl    optionally substituted by C1–3 alkyl and C1–5 alkoxy, each being    optionally be partially or fully halogenated;-   R⁶ is chosen from-   a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkyl branched or    unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), heterocycle selected from    morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl or phenyl,    each alkyl, alkenyl, heterocycle and phenyl are optionally    substituted by one to three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono    or diC₁₋₃ alkyl amino, amino or C₁₋₅ alkoxycarbonyl;    wherein each R₆ is further optionally covalently attached to groups    chosen from:    -   hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl,        benzyloxy, phenylC₀₋₄ alkyl, piperazinylC₀₋₄ alkyl, piperidinyl        C₀₋₄alkyl, pyrrolidinylC₀₋₄ alkyl, morpholinylC₀₋₄ alkyl,        triazolyl C₀₋₄alkyl, imidazolyl C₀₋₄alkyl and pyridinyl        C₀₋₄alkyl, each above-listed heterocycle, heteroaryl and phenyl        group is optionally substituted by one to three hydroxy, oxo,        C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl, amino, NR₇R₈—C(O)—        or C₁₋₄ acyl;-   each R₇ and R₈ are independently hydrogen, phenylC₀₋₂alkyl    optionally subtituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino,    or R₇ and R₈ are C₁₋₅ branched or unbranched alkyl optionally    substituted by C₁₋₄ alkoxy, hydroxy or mono or diC₁₋₃ alkyl amino;-   R^(b) is chosen from hydrogen, C1–5 alkyl, C3–7 cycloalkylC0–2    alkyl, aryl, C1–5 alkoxy, amino, C1–5 alkylamino, C1–3 dialkylamino,    C1–3 acyl, C1–5 alkoxycarbonyl, C1–3 acyloxy, C1–3 acylamino, C1–3    sulphonylamino, hydroxy, halogen, trifluoromethyl, nitro, nitrile;-   or R^(b) is chosen from pyrrolidinyl, pyrrolinyl, morpholinyl,    thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone,    piperidinyl, piperazinyl, piperidinonyl, tetrahydropyrimidonyl,    aziridinyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl,    tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl,    pyrazinyl and pyridazinyl.

In yet still another embodiment, there are provided compounds of theformula (I) as described immediately above and wherein

-   Ar¹ is formula (A) or (B)

wherein:when Ar¹ is formula (A) then:

-   R¹ is NH₂, J-N(R^(a))—(CH₂)_(m)—, NH₂C(O)—, J-N(R^(a))—C(O)—,    J-S(O)₂—N(R^(a))—, J-N(R^(a))—S(O)₂— or heterocycle-(CH₂)₁₋₂—    wherein the heterocycle is chosen from pyrrolidinyl, morpholinyl and    piperazinyl each optionally substituted by C1–4 alkyl, and J is C₁₋₅    alkyl optionally substituted by R^(b);    or    when Ar¹ is formula (B) then:-   R¹ is hydrogen or halogen;-   R₂ is independently chosen from C1–5 alkyl, C3–6 cycloalkyl    optionally substituted by C1–3 alkyl and C1–5 alkoxy, each being    optionally partially or fully halogenated;-   R⁶ is chosen from-   a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkyl branched or    unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), heterocycle selected from    morpholinyl, piperazinyl, piperidinyl and pyrrolidinyl or phenyl,    each alkyl, alkenyl, heterocycle and phenyl are optionally    substituted by one to three hydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono    or diC₁₋₃ alkyl amino, amino or C₁₋₅ alkoxycarbonyl;    wherein each R₆ is further optionally covalently attached to groups    chosen from:    -   hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl,        benzyloxy, phenylC₀₋₄ alkyl, piperazinyl, piperazinylC₁₋₂ alkyl,        piperidinyl, piperidinyl C₁₋₂alkyl, pyrrolidinyl, pyrrolidinyl        C₁₋₂ alkyl, morpholinyl, morpholinylC₁₋₂ alkyl, triazolyl,        triazolyl C₁₋₂alkyl, imidazolyl, imidazolyl C₁₋₂alkyl, pyridinyl        and pyridinyl C₁₋₂alkyl, each above-listed heterocycle,        heteroaryl and phenyl group is optionally substituted by one to        three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅        alkoxycarbonyl, amino, NR₇R₈—C(O)— or C₁₋₄ acyl.

In yet still another embodiment, there are provided compounds of theformula (I) as described immediately above and wherein

-   Ar¹ is formula (A) or (B)

-   and R² is chosen from

when Ar¹ is formula (A) then:

-   when R¹ is J-S(O)₂—N(R^(a))— or J-N(R^(a))—S(O)₂— then J is C₁₋₃    alkyl;    and-   when R¹ is NH₂, J-N(R^(a))—(CH₂)_(m)—, NH₂C(O)—, J-N(R^(a))—C(O)—,    or heterocycle-(CH₂)₁₋₂— wherein the heterocycle is chosen from    pyrrolidinyl, morpholinyl, piperazinyl or C1–4alkylpiperazinyl, then-   J is C1–3 alkyl optionally substituted by R^(b).

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   R^(b) is chosen from hydrogen, C1–5 alkyl, C3–6 cycloalkylC0–2    alkyl, phenyl, C1–5 alkoxy, amino, C1–5 alkylamino, C1–3    dialkylamino, C1–3 acyl, C1–5 alkoxycarbonyl, C1–3 acyloxy, C1–3    acylamino, hydroxy, halogen;-   or R^(b) is chosen from morpholinyl, thiomorpholinyl,    thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, piperidinyl,    piperidinonyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl.

In yet another embodiment, there are provided compounds of the formula(I) as described immediately above and wherein

-   R^(b) is chosen from amino, C1–5 alkylamino, C1–3 dialkylamino;-   or R^(b) is chosen morpholinyl, piperidinyl and pyridinyl.

In yet still another embodiment, there are provided compounds of theformula (I) as described immediately above and wherein

-   Ar¹ is formula (A).

In yet still another embodiment, there are provided compounds of theformula (I) as described above and wherein

-   Ar¹ is formula (B).

In yet another embodiment, there are provided compounds of the formula(I) as described above and wherein

-   Ar¹ is

The following are representative compounds of the invention which havebeen made according to the general schemes and working examples below:

TABLE I

1-Methyl-7-(pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-phenyl)-amide

7-[2-(2-Diethylamino-ethylamino)-pyrimidn-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Cyclopropylamino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(4-Methoxy-benzylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(3-Dimethylamino-propylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(3-Dimethylamino-2,2-dimethyl-propylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Dimethylamino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(6-methyl-2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-pyrrolidin-1-yl-ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(piperidin-4-ylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

4-{4-[2-(5-tert-Butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indole-7-yloxy]-pyrimidin-2-ylamino}-piperidine-1-carboxylicacid tert-butyl ester

7-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-pyrimidin-4-yloxy}-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[6-methyl-2-(4-methyl-piperazin-1-yl)pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methaesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2-Dimethylamino-ethoxy)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methaesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2-Dimethylamino-ethoxy)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-pyrrolidin-1-yl-ethoxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(1-methyl-piperidin-4-yloxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2-Dimethylamino-ethoxy)-6-methyl-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylcarbamoyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid[5-tert-butyl-3-(2-dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide

7-[2-(2-Dimethylamino-ethylcarbamoyl)-pyridin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid[5-tert-butyl-3-(2-dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid]5-tert-butyl-2-methoxy-3-(2-morpholin-4-yl-ethylcarbamoyl)-phenyl]-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-carbamoyl--2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-3-methylcarbamoyl-phenyl)-amide

1-Methyl-7-(2-vinyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(1,2-Dihydroxy-ethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(morpholin-4-ylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-ylmethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Dimethylaminomethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methanecarbamoyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Benzyloxymethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-3-morpholin-4-ylmethyl-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid[5-tert-butyl-2-methoxy-3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-dimethylaminomethyl-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(3-amino-5-tert-butyl-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-dibenzylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-2-methylsulfamoyl-phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-[1,3]dioxolan-2-yl-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-2-methoxy-3-methylaminomethyl-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-2-methoxy-3-pyrrolidin-1-ylmethyl-phenyl)-amide

1-Methyl-7-{2-[methyl-(1-methyl-piperidin-4-yl)-amino]-pyrimidin-4-yloxy}-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Hydroxymethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amideand

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid[5-tert-butyl-2-methoxy-3-(2-morpholin-4-yl-ethylamino)-phenyl]-amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-piperazin-1-yl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide

1-Methyl-7-[2-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Methoxy-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(4-tert-Butyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-{2-[2-(4-methyl-piperazin-1-yl)-ethyl]-pyrimidin-4-yloxy}-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-pyrrolidin-1-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2-Dimethylamino-ethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

7-{2-[2-(4-tert-Butyl-piperazin-1-yl)-ethyl]-pyrimidin-4-yloxy}-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(4-tert-Butyl-piperazin-1-ylmethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-pyrrolidin-1-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2,6-Dimethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Ethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Amino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-pyrrolidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-piperidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-ylmethyl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-2-methoxy-phenyl)-amide

7-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-carbamoyl-2-methoxy-phenyl)-amide

1-Methyl-7-[2-((1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-[1,4]diazepan-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-[1,4]Diazepan-1-ylpyridin-4-yloxy)-1-methyl-1-H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-piperazin-1-yl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-trideuterio-7-(2-piperazin-1-yl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(Hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-trideuterio-7-[2-(4-methyl-piperazin-1-yl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide

7-[2-((S)-3-Dimethylamino-pyrrolidin-1-yl)-pyridin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide

7-[2-((S)-3-Dimethylamino-pyrrolidin-1-yl)-pyridin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide

1-Methyl-7-[2-(4-methyl-piperazine-1-carbonyl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(piperazine-1-carbonyl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amideor the pharmaceutically acceptable salts, acids, esters or isomersthereof.

Preferred compounds of the invention are listed in table II.

TABLE II

1-Methyl-7-(pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-carbamoyl-2-methoxy-phenyl)-amide

1-Methyl-7-(2-pyrrolidin-1-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-{[(2-Dimethylamino-ethyl)-methyl-amino]-methyl}-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-2-methoxy-phenyl)-amide

7-[2-(4-tert-Butyl-piperazin-1-ylmethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Dimethylaminomethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-{2-[2-(4-tert-Butyl-piperazin-1-yl)-ethyl]-pyrimidin-4-yloxy}-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-pyrrolidin-1-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(3-Dimethylamino-propylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(3-Dimethylamino-2,2-dimethyl-propylamino)-pyrimidn-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Dimethylamino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(6-methyl-2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-pyrrolidin-1-yl-ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(piperidin-4-ylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-pyrimidin-4-yloxy}-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-{2-[2-(4-methyl-piperazin-1-yl)-ethyl]-pyrimidin-4-yloxy}-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2-Dimethylamino-ethoxy)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-pyrrolidin-1-yl-ethoxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(1-methyl-piperidin-4-yloxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(4-tert-Butyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylcarbamoyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid[5-tert-butyl-3-(2-dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide

7-[2-(2-Dimethylamino-ethylcarbamoyl)-pyridin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid[5-tert-butyl-3-(2-dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid[5-tert-butyl-2-methoxy-3-(2-morpholin-4-yl-ethylcarbamoyl)-phenyl]-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-carbamoyl-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-3-methylcarbamoyl-phenyl)-amide

1-Methyl-7-(2-pyrrolidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(1,2-Dihydroxy-ethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(morpholin-4-ylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-ylmethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Dimethylaminomethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylcarbamoyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-piperidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-3-morpholin-4-ylmethyl-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid[5-tert-butyl-2-methoxy-3-(4-methyl-piperazin-1-ylmethyl)phenyl]-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-dimethylaminomethyl-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(3-amino-5-tert-butyl-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-ylmethyl)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-2-methoxy-3-methylaminomethyl-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-2-methoxy-3-pyrrolidin-1-ylmethyl-phenyl)-amide

1-Methyl-7-{2-[methyl-(1-methyl-piperidin-4-yl)-amino]-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Hydroxymethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid[5-tert-butyl-2-methoxy-3-(2-morpholin-4-yl-ethylamino)-phenyl]-amideand

1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amideor the pharmaceutically acceptable salts, acids, esters or isomersthereof.

The following are representative compounds of the invention which can bemade according to the general schemes and working examples below:

TABLE III

7-(pyrimidin-4-yloxy)-benzo[b]thiophene-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(Pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(Pyrimidin-4-yloxy)-benzofuran-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(pyrimidin-4-ylsulfanyl)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(pyrimidin-4-ylamino)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(pyridin-3-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Benzylamino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-{2-[(pyridin-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2-Imidazol-1-yl-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-[1,2,3]triazol-1-yl-ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(3-Dimethylamino-propylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid[2-methoxy-5-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-phenyl]-amide

7-{2-[(2-Dimethylamino-ethyl)-methyl-amino]-pyrimidin-4-yloxy}-1-methyl-1H-indole-2-carboxylicacid (4-chloro-2-methoxy-5-trifluoromethyl-phenyl)-amide

7-[2-(4-Acetyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (4-chloro-2-methoxy-5-trifluoromethyl-phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (2-methoxy-5-trifluoromethoxy-phenyl)-amide

7-[2-(4-Dimethylamino-piperidin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(3-Dimethylamino-pyrrolidin-1-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(1-methyl-piperidin-4-ylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(1-Acetyl-piperidin-4-ylamino)-pyrimidin-4-ylozy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

7-[2-(2-Imidazol-1-yl-ethoxy)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(2-Imidazol-1-yl-ethoxy)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid(4-chloro-2-methoxy-5-trifluoromethyl-phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-2-methoxy-3-methylcarbamoyl-phenyl)-amide

7-(2-Amino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-carbamoyl-2-methoxy-phenyl)-amide

7-(2-Amino-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid[5-tert-butyl-3-(2-dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-dimethylaminomethyl-2-methoxy-phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-2-methoxy-3-pyrrolidin-1-ylmethyl-phenyl)-amide

7-[2-(2-Dimethylamino-ethylamino)-pyrimidin-4-yloxy]-1-mnethyl-1H-indole-2-carboxylicacid (5-tert-butyl-2-methoxy-3-morpholin-4-ylmethyl-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (4-chloro-2-methoxy-5-trifluoromethyl-phenyl)-amide

7-[2-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-(2-Carbamoyl-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (2-methoxy-3-morpholin-4-ylmethyl-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (2-methoxy-3-morpholin-4-ylmethyl-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-(2-morpholin-4-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

7-(1′-tert-Butyl-1′,2′,3′,4′,5′,6′-hexahydro-]2,4′]bipyridinyl-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-(2-methylaminomethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-(2-pyrrolidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid(2-methoxy-3-morpholin-4-ylmethyl-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (3-dimethylaminomethyl-2-methoxy-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-(2-pyrrolidin-1-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (2-methoxy-3-pyrrolidin-1-ylmethyl-5-trifluoromethyl-phenyl)-amide

7-(2-Dimethylaminomethyl-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid[2-methoxy-3-(4-methyl-piperazin-1-ylmethyl)-5-trifluoromethyl-phenyl]-amide

7-(2-Dimethylaminomethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

7-(2-Dimethylaminomethyl-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-ylmethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

7-(2-Dimethylaminomethyl-pyrimidin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid(3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-[2-(2-morpholin-4-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid[3-methanesulfonylamino-2-methoxy-5-(1-methyl-cyclopropyl)-phenyl]-amide

1-Methyl-7-[2-(1-methyl-piperidin-4-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

7-[2-(1-Cyclopropyl-piperidin-4-yl)-pyrimidin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

1-Methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (3-dimethylaminomethyl-2-methoxy-5-trifluoromethyl-phenyl)-amide

1-Methyl-7-[2-(1-methyl-pyrrolidin-3-ylamino)-pyridin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amideor the pharmaceutically acceptable salts, acids, esters or isomersthereof.

In all the compounds disclosed hereinabove in this application, in theevent the nomenclature is in conflict with the structure, it shall beunderstood that the compound is defined by the structure.

Of particular importance according to the invention are compounds offormula (I), wherein Ar₁, X, Y, Q, W, R³, R⁴, R⁵, R⁶ and R^(y) have themeaning indicated, for use as pharmaceutical compositions with ananti-cytokine activity.

The invention also relates to the use of a compound of formula (I),wherein Ar₁, X, Y, Q, W, R³, R⁴, R⁵, R⁶ and R^(y) have the meaningindicated, for preparing a pharmaceutical composition for the treatmentand/or prevention of a cytokine mediated disease or condition.

The invention also relates to pharmaceutical preparations, containing asactive substance one or more compounds of formula (I), wherein Ar₁, X,Y, Q, W, R³, R⁴, R⁵, R⁶ and R^(y) have the meanings indicated, or thepharmaceutically acceptable derivatives thereof, optionally combinedwith conventional excipients and/or carriers.

Compounds of the invention also include their isotopically-labelledforms. An isotopically-labelled form of an active agent of a combinationof the present invention is identical to said active agent but for thefact that one or more atoms of said active agent have been replaced byan atom or atoms having an atomic mass or mass number different from theatomic mass or mass number of said atom which is usually found innature. Examples of isotopes which are readily available commerciallyand which can be incorporated into an active agent of a combination ofthe present invention in accordance with well established procedures,include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,fluorine and chlorine, e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S, ¹⁸F, and ³⁶Cl, respectively. An active agent of a combination ofthe present invention, a prodrug thereof, or a pharmaceuticallyacceptable salt of either which contains one or more of theabove-mentioned isotopes and/or other isotopes of other atoms iscontemplated to be within the scope of the present invention.

The invention includes the use of any compounds of described abovecontaining one or more asymmetric carbon atoms may occur as racematesand racemic mixtures, single enantiomers, diastereomeric mixtures andindividual diastereomers. All such isomeric forms of these compounds areexpressly included in the present invention. Each stereogenic carbon maybe in the R or S configuration, or a combination of configurations.

Some of the compounds of formula (I) can exist in more than onetautomeric form. The invention includes methods using all suchtautomers. All terms as used herein in this specification, unlessotherwise stated, shall be understood in their ordinary meaning as knownin the art. For example, “C₁₋₄alkoxy” is a C₁₋₄alkyl with a terminaloxygen, such as methoxy, ethoxy, propoxy, butoxy. All alkyl, alkenyl andalkynyl groups shall be understood as being branched or unbranched wherestructurally possible and unless otherwise specified. Other morespecific definitions are as follows:

The term “aroyl” as used in the present specification shall beunderstood to mean “benzoyl” or “naphthoyl”.

Carbocycles include hydrocarbon rings containing from three to twelvecarbon atoms. These carbocycles may be either aromatic either aromaticor non-aromatic ring systems. The non-aromatic ring systems may be mono-or polyunsaturated. Preferred carbocycles include but are not limited tocyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl,benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl,decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certainterms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be usedinterchangeably.

The term “heterocycle” refers to a stable nonaromatic 4–8 membered (butpreferably, 5 or 6 membered) monocyclic or nonaromatic 8–11 memberedbicyclic heterocycle radical which may be either saturated orunsaturated. Each heterocycle consists of carbon atoms and one or more,preferably from 1 to 4 heteroatoms chosen from nitrogen, oxygen andsulfur. The heterocycle may be attached by any atom of the cycle, whichresults in the creation of a stable structure. Unless otherwise stated,heterocycles include but are not limited to, for example pyrrolidinyl,pyrrolinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl,1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl,tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene sulfoxide,pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxideand tetramethylene sulfone.

The term “heteroaryl” shall be understood to mean an aromatic 5–8membered monocyclic or 8–11 membered bicyclic ring containing 1–4heteroatoms such as N, O and S. Unless otherwise stated, suchheteroaryls include aziridinyl, thienyl, furanyl, isoxazolyl, oxazolyl,thiazolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyranyl, quinoxalinyl,indolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzothienyl,quinolinyl, quinazolinyl, naphthyridinyl, indazolyl, triazolyl,pyrazolo[3,4-b]pyrimidinyl, purinyl, pyrrolo[2,3-b]pyridinyl,pyrazolo[3,4-b]pyridinyl, tubercidinyl, oxazo[4,5-b]pyridinyl andimidazo[4,5-b]pyridinyl.

The term “heteroatom” as used herein shall be understood to mean atomsother than carbon such as O, N, S and P.

In all alkyl groups or carbon chains one or more carbon atoms can beoptionally replaced by heteroatoms: O, S or N, it shall be understoodthat if N is not substituted then it is NH, it shall also be understoodthat the heteroatoms may replace either terminal carbon atoms orinternal carbon atoms within a branched or unbranched carbon chain. Suchgroups can be substituted as herein above described by groups such asoxo to result in defintions such as but not limited to: alkoxycarbonyl,acyl, amido and thioxo.

The term “aryl” as used herein shall be understood to mean aromaticcarbocycle or heteroaryl as defined herein. Each aryl or heteroarylunless otherwise specified includes it's partially or fully hydrogenatedderivative. For example, quinolinyl may include decahydroquinolinyl andtetrahydroquinolinyl, naphthyl may include it's hydrogenated derivativessuch as tetrahydranaphthyl. Other partially or fully hydrogenatedderivatives of the aryl and heteroaryl compounds described herein willbe apparent to one of ordinary skill in the art.

As used herein, “nitrogen” and “sulfur” include any oxidized form ofnitrogen and sulfur and the quaternized form of any basic nitrogen. Forexample, for an —S—C₁₋₆ alkyl radical, unless otherwise specified, thisshall be understood to include —S(O)—C₁₋₆ alkyl and —S(O)₂—C₁₋₆ alkyl.

The term “halogen” as used in the present specification shall beunderstood to mean bromine, chlorine, fluorine or iodine, preferablyfluorine. The definitions “partially or fully halogenated”; partially orfully fluorinated; “substituted by one or more halogen atoms”, includesfor example, mono, di or tri halo derivatives on one or more carbonatoms. For alkyl, a nonlimiting example would be —CH₂CHF₂, —CF₃ etc.

The compounds of the invention are only those which are contemplated tobe ‘chemically stable’ as will be appreciated by those skilled in theart. For example, a compound which would have a ‘dangling valency’, or a‘carbanion’ are not compounds contemplated by the inventive methodsdisclosed herein.

The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (I). A “pharmaceutically acceptable derivative”refers to any pharmaceutically acceptable salt or ester, or any othercompound which, upon administration to a patient, is capable ofproviding (directly or indirectly) a compound useful for the invention,or a pharmacologically active metabolite or pharmacologically activeresidue thereof. A pharmacologically active metabolite shall beunderstood to mean any compound of the invention capable of beingmetabolized enzymatically or chemically. This includes, for example,hydroxylated or oxidized derivative compounds of the formula (I).

Pharmaceutically acceptable salts include those derived frompharmaceutically acceptable inorganic and organic acids and bases.Examples of suitable acids include hydrochloric, hydrobromic, sulfuric,nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic,salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric,methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric andbenzenesulfonic acids. Other acids, such as oxalic acid, while notthemselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsand their pharmaceutically acceptable acid addition salts. Salts derivedfrom appropriate bases include alkali metal (e.g., sodium), alkalineearth metal (e.g., magnesium), ammonium and N—(C₁–C₄ alkyl)₄ ⁺ salts.

In addition, within the scope of the invention is use of prodrugs ofcompounds of the formula (I). Prodrugs include those compounds that,upon simple chemical transformation, are modified to produce compoundsof the invention. Simple chemical transformations include hydrolysis,oxidation and reduction. Specifically, when a prodrug is administered toa patient, the prodrug may be transformed into a compound disclosedhereinabove, thereby imparting the desired pharmacological effect.

General Synthetic Methods

The invention additionally provides for methods of making the compoundsof the formula (I). The compounds of the invention may be prepared bythe general methods and examples presented below, and methods known tothose of ordinary skill in the art. Further reference in this regard maybe made to U.S. Pat. No. 6,358,945, U.S. application Ser. Nos.09/714,539, 09/834,797, 10/120,028, 10/143,322 and 10/147,675. U.S.application Ser. No. 10/264,689 teaches additional methods forpreparation of sulfonamide intermediates. Each of the aforementionedU.S. cases are incorporated in their entirety. In all schemes, unlessotherwise specified, Ar¹, X, Y, W and R³–R⁶ in the formulas shown belowshall have the meanings defined for these groups in the definition ofthe formula (I) of the invention, described hereinabove. Intermediatesused in the syntheses below are either commercially available or easilyprepared by methods known to those skilled in the art. Reaction progressmay be monitored by conventional methods such as thin layerchromatography (TLC). Intermediates and products may be purified bymethods known in the art, including column chromatography, HPLC orrecrystallization.

Compounds of the invention where Q is a carbon atom, may be prepared asdescribed in Schemes I and II. Compounds of the invention wherein Q is anitrogen atom, may be prepared by analogous methods which will beapparent to one of ordinary skill in the art.

As illustrated in Scheme I an amine bearing Ar¹ is coupled withcarboxylic acid III, where P is a protecting group, using standardcoupling conditions known in the art (see for example M. Bodanszky,1984, The Practice of Peptide Synthesis, Springer-Verlag). For example,one may couple III and II by treating with1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC)followed by 1-hydroxybenzotriazole hydrate (HOBT) in a suitable solventsuch as DMF. Removal of the protecting group P to provide V may beachieved by standard procedures known in the art. For example, if P is abenzyl group, it may be removed by treatment of IV with hydrogen gas inthe presence of a catalyst such as palladium on carbon in a suitablesolvent such as EtOH. The resulting intermediate V may then be coupledwith the desired halo heterocycle VI (Z=halogen) bearing R⁶ in thepresence of a suitable base to provide I. Ar¹ and R⁶ may be furthermodified by standard synthetic methods known in the art to produceadditional compounds of formula (I). Several examples are described inthe Synthetic Examples section below.

In a modification of the above method, the order of coupling VI andAr¹NH₂ with the central heterocycle may be reversed. This is illustratedin Scheme II.

As illustrated above, the ester VII (R=lower alkyl such as methyl orethyl, P=a protecting group) is deprotected as described above and theresulting intermediate VIII is coupled, as described above to provideester IX. This is hydrolyzed using standard hydrolysis conditions andthe resulting acid coupled with Ar¹NH₂ to provide I. As above, Ar¹ andR⁶ may be further modified by standard synthetic methods known in theart to produce additional compounds of formula (I). Several examples aredescribed in the Synthetic Examples section below.

SYNTHETIC EXAMPLES Example 1 Synthesis of1-methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

For a similar procedure to form the indole core, see R. Albrecht et al.Eur. J. Med. Chem. Chim. Ther. 1985, 20, 59–60.

In a 1 L 3-neck round-bottom flask equipped with a condenser andmechanical stirrer were placed the 2-nitro-3-methylphenol (50.8 g, 331.5mmol), 500 mL anhydrous acetonitrile and potassium carbonate (57.3 g,414.3 mmol). The yellow solution became orange. While stirring, benzylbromide (39.4 mL, 331.5 mmol) was added slowly via syringe, then themixture was heated to gentle reflux overnight and allowed to cool. Anorange precipitates formed. The reaction was quenched with water andextracted with EtOAc three times. The combined organic extracts werewashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo.The desired benzyl ether was obtained as a yellow oil, 80.7 g(quantitative).

Potassium tert-Butoxide solution (1.0 M in THF, 100 mL, 100 mmol) wasplaced in a 1000 mL round-bottom flask under inert atmosphere. Ether(370 mL) was then added causing the solution to become murky. This wasfollowed by addition of diethyl oxalate (14.0 mL, 103.1 mmol). Thesolution became yellow. After stirring 10 min, the benzyl ether fromabove (24.3 g, 99.9 mmol) was added directly to the flask and themixture was left standing overnight. The reaction was heated to a gentlereflux for 18 h then left at room temperature overnight. An orangeprecipitate had formed. The precipitated product was filtered through aBuchner funnel and washed ether providing 29.1 g of the desiredcondensation product as the potassium salt.

In a 1 L 3-neck round-bottom flask equipped with a condenser andmechanical stirrer were placed the potassium salt from above (29.1 g,76.3 mmol) and 250 mL glacial acetic acid. Iron powder (25.6 g, 458.0mmol) was added and the reaction was stirred at 100° C. for 1 h and thenallowed to cool. EtOAc (800 mL) was added and the mixture was filteredthrough diatomaceous earth and left standing overnight. A saturatedaqueous solution of NaHCO₃ was added slowly to the filtrate. A lot ofbubbling was observed. The layers were separated and the organic phasewas washed with water and brine, dried (MgSO₄), filtered andconcentrated in vacuo. The resulting product was dried under high vacuumovernight. It was then decolorized with charcoal by heating in anEtOH/MeOH mixture, filtered and concentrated in vacuo, providing 7.5 gof the desired indole ester.

The indole ester (19.0 g, 64.3 mmol) was dissolved in 160 mL anhydrousDMF at room temperature and treated with sodium hydride (4.0 g, 100mmol), added portionwise. Once the mixture cooled back to roomtemperature, iodomethane (6.2 mL, 100 mmol) was added. Vigorous heatingwas again observed. One extra equivalent of iodomethane was added. Themixture was left stirring overnight and was then partitioned betweenEtOAc and saturated aqueous ammonium chloride solution. The organicphase was washed with water twice, then brine, dried (MgSO₄), filteredand concentrated in vacuo leaving a brown oil. The product was purifiedby column chromatography on SiO₂ using 10, 20% EtOAc in hexanes aseluent. The 1-methyl indole ester (17.2 g, mixture of methyl and ethylesters) was isolated as a pale yellow solid.

The above ester (4.01 g, 13.0 mmol) was placed in 100 mL THF and treatedwith LiOH hydrate (1.1 g, 26.0 mmol) dissolved in 15 mL water. Theresulting slightly murky solution was left stirring vigorously at roomtemperature for 3 days. It was then acidified with dilute aqueous HCl topH˜1 and extracted with EtOAc twice. The extracts were washed with brinetwice and dried (MgSO₄), filtered and concentrated in vacuo. Theresulting carboxylic acid (3.75 g, quantitative) was obtained as a whitesolid.

The carboxylic acid (0.93 g, 3.31 mmol) in 10 mL anhydrous DMF at roomtemperature under N₂ was treated withO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (1.71 g, 4.50 mmol), triethylamine (1.75 mL,12.57 mmol) and catalytic 1-hydroxy-7-azabenzotriazole (HOAt) (231 mg,1.70 mmol). After 10 min at room temperature the aniline hydrochloridesalt was added in one portion. The mixture was left to stir at roomtemperature overnight, then diluted with EtOAc, washed with water,dilute aqueous HCl, water again and finally brine. The solution was thendried (MgSO₄), filtered and concentrated in vacuo leaving a brown foam.The product was purified by SiO₂ column chromatography using EtOAc inhexane eluent mixtures providing the desired amide (1.05 g) as a whitesolid.

The above amide (1.00 g, 1.87 mmol) was dispersed in 25 mL absoluteEtOH. A slurry of 20% Pd(OH)₂ in EtOH was added by pipet (230 mg). Themixture was stirred under an atmosphere of H₂. After 3 h the reactionwas filtered through diatomaceous earth and concentrated in vacuo,providing the debenzylated hydroxy indole amide (843 mg) as a lightyellow solid.

The hydroxy indole amide (824 mg, 1.85 mmol) was dissolved in 10 mLanhydrous acetonitrile. DBU (0.277 mL, 1.85 mmol) was added, followed by2,4-dichloropyrimidine (276 mg, 1.85 mmol) and the reaction was leftstirring at room temperature for 1.5 h, then concentrated in vacuo. Theresidue was loaded on a SiO₂ column and purified, eluting with EtOAc inhexanes mixtures. The 2-chloropyrimidinyl ether (367 mg) was isolated asa white solid.

The 2-chloropyrimidinyl ether (104 mg, 0.186 mmol) was placed in 1.5 mLanhydrous THF followed by 1-methylpiperazine (0.042 mL, 0.375 mmol). Themixture was stirred in a sealed tube overnight at 75° C. It was thenallowed to cool, then water was added and the mixture was extracted withCH₂Cl₂ twice. The combined organic extracts were dried (MgSO₄), filteredand concentrated in vacuo, leaving an orange foam. This was dissolved inacetonitrile and heated until product precipitated as an off-white solidthat was collected by filtration through vacuum Buchner funnel and airdried. The title compound (80 mg) was obtained as an off-white solid.

Example 2 Synthesis of1-methyl-7-[2-(2-morpholin-4-yl-ethylamino)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

The 2-chloropyrimidinyl ether intermediate (75 mg, 0.13 mmol) (seeExample 1) was dissolved in 1.0 mL anhydrous THF, treated withtriethylamine (21 uL, 0.15 mmol) and 4-aminoethylmorpholine (18 uL, 0.13mmol). The solution was placed in a sealed tube and stirred in a 75° C.bath overnight. The reaction was then allowed to cool, partitionedbetween water and EtOAc, and the aqueous phase was extracted with moreEtOAc. The combined organic extracts were dried (MgSO₄), filtered, andconcentrated in vacuo leaving a yellow foam (92 mg). The product waspurified by SiO₂ column chromatography, using MeOH in dichloromethaneeluent. The resulting white foam was suspended in a little acetonitrileand heated to boiling until it dissolved. Upon cooling slowly cool toroom temperature, crystals of the desired amino-pyriminyl etherprecipitated out. These were collected by vacuum filtration with aBuchner finnel providing the title compound (57 mg), mp: 201–202° C.

Example 3 Synthesis of1-methyl-7-(2-morpholin-4-ylmethyl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

The 2-chloropyrimidinyl ether intermediate (500 mg, 0.896 mmol) (seeExample 1), vinyltributyltin (600 mg, 1.89 mmol), BHT (20 mg), and(PPh₃)₄Pd (50 mg, 0.045 mmol) were suspended in degassed toluene (10 mL)under argon and heated to 115° C. for 3 h. The reaction mixture wascooled, diluted with EtOAc (100 mL), washed with brine (10 mL), anddried over MgSO₄. Silica gel chromatography (gradient elution, 0% to 80%EtOAc in hexanes) provided the desired 2-vinylpyrimidinyl etherintermediate (302 mg, 61%) as a pale yellow solid.

The 2-vinylpyrimidinyl ether (152 mg, 0.277 mmol) was dissolved in 8:1acetone/water (10 mL). N-methylmorpholine-N-oxide (150 mg, 1.28 mmol)and OSO₄ (50 μL of a 2.5 wt % solution in tert-butanol) were added andthe reaction was stirred at room temperature for 6 h. Sodium sulfite(250 mg) in water (20 mL) was added, and the solution was stirred atroom temperature for 15 min. The reaction mixture was extracted withdichloromethane (4×20 mL), and the combined organic extracts dried overNa₂SO₄ and concentrated. Recrystallization from dichloromethane/hexanesprovided the desired diol as a white powder (105 mg, 65%).

To a vigorously stirred suspension of silica gel (20 g ) indichloromethane (80 mL) was added a solution of sodium periodate (1.40g, 6.55 mmol) in water (10 mL) over two min. A solution of the diol(1.25 g, 2.14 mmol) in dichloromethane (10 mL) was then added in oneportion. After stirring at room temperature for 2 h, the mixture wasfiltered through a sintered glass frit with copious dichloromethane andEtOAc washings. The filtrate was dried over MgSO₄ and concentrated toprovide the desired aldehyde as a pale brown solid (1.08 g, 91%).

To a vigorously stirred solution of the aldehyde (52 mg, 0.094 mmol),morpholine (200 μL), and acetic acid (150 μL) in 1,2-dichloroethane (4mL) was added sodium triacetoxyborohydride (100 mg, 0.472 mmol). Theresulting mixture was stirred at room temperature for 16 h. SaturatedNaHCO₃ (1 mL) and brine (3 mL) were added and the mixture was stirredfor a further 10 min. Extraction with dichloromethane (3×20 mL) wasfollowed by drying (MgSO₄), and removal of the solvent. Silica gelchromatography (gradient elution, 0 to 10% MeOH in dichloromethane, 0.3%NH₄OH) provided the title compound as an off-white solid (40 mg, 68%).

Example 4 Synthesis of1-methyl-7-(pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

The 2-chloropyrimidinyl ether intermediate (100 mg, 0.179 mmol) (seeExample 1) was dissolved in a mixture of EtOH and CH₃CN (4:1, total 10mL, using heat gun to complete dissolution). The reaction was cooled toroom temperature under N₂ then 10% palladium-on-carbon (35 mg) was addedand the reaction vessel was purged with H₂ several times. The reactionwas stirred under H₂ (balloon). After stirring at room temperature for 4h the reaction was filtered through diatomaceous earth and washed withCH₃CN. The solvents were removed in vacuo and the residue dissolved inCH₂Cl₂ (not totally soluble) and purified by flash column chromatographyusing EtOAc/hexanes as eluent mixtures, providing 24 mg of the titlecompound.

Example 5 Synthesis of1-methyl-7-[2-(2-morpholin-4-yl-ethoxy)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

The chloropyrimidinyl ether intermediate (see Example 1) (0.250 g, 0.448mmol) was dissolved in 5 mL CH₃CN in a 15 mL pressure tube. In a singleportion, a mixture of 4-(2-hydroxyethyl)morpholine (0.080 g, 0.61 mmol)and DBU (0.11 g, 0.73 mmol) were added. The tube was washed down with 5mL CH₃CN, sealed, and heated to about 95° C. (oil bath temp) for 48 h.The oil bath was raised to 110° C. and heating continued another 18 h.The reaction was allowed to cool, stripped to an amber oil andpartitioned between EtOAc and water. The organic phase was washed withwater, then brine, and dried over MgSO₄. The organic layer was strippedagain to approximately 300 mg of amber oil, absorbed onto silica, andthe product purified by flash column chromatography on SiO₂ using 5–25%iPrOH in CH₂Cl₂ as eluents. Concentration of the product-rich fractionsafforded 40 mg of the title compound.

Example 6 Synthesis of1-methyl-7-(2-methylcarbamoyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

To a solution of the indole ester intermediate (see Example 1) (1.26 g,˜4 mmol) in 25 mL, of EtOAc was added 10% Pd/C (250 mg). The reactionvessel was purged with N₂. and 1,4-cyclohexadiene (1.92 mL, 20.5 mmol)was added via syringe. The reaction mixture was heated to reflux for 5h, then cooled to room temperature, filtered through a pad ofdiatomaceous earth, and rinsed with EtOAc. The resulting solution wasevaporated to afford a pink solid which was purified by columnchromatography on SiO₂ (4:1 hexanes-EtOAc) to give 740 mg of the desired7-hydroxyindole intermediate.

To a solution of the 7-hydroxyindole (200 mg, 0.912 mmol) in 2 mL of dryTHF was added NaH (40 mg of a 60% dispersion in mineral oil) resultingin a deep blue solution.

A solution of 4chloropyridine-2carboxylic acid t-butyl ester (256 mg,1.20 mmol) in 1 mL of DMF was added and the mixture was heated to 120°C. under N₂ for 5 h. After cooling down, the reaction mixture wasdiluted with EtOAc, washed with water, brine, dried (Na₂SO₄) andfiltered. After removal of solvents, the residue was purified by columnchromatography on silica gel, eluting with 4:1 hexanes-EtOAc to give 50mg of the desired diester.

The above diester (170 mg, 0.43 mmol) was dissolved in 4 mL CH₂Cl₂, and1,3-dimethoxybenzene and 1 mL of TFA were added and the reaction wasstirred overnight. After removal of the solvents, water was added to theoily residue and the pH adjusted to 3–4 with NaHCO₃ and extracted withCH₂Cl₂. The extracts were washed with brine, dried (Na₂SO₄) andfiltered. After removal of the solvents, the desired carboxylic acid wasused in next step without further purification.

To a solution of the carboxylic acid (160 mg, 0.47 mmol) in 2 mL of DMFwere added Hunig's base (200 uL, 1.15 mmol), HATU (226 mg, 0.576 mmol),HOAt (8.2 mg, 0.06 mmol) and MeNH₂ (0.5 mL of a 2.0 M solution in THF, 1mmol) successively. The reaction was stirred overnight, then dilutedwith EtOAc, washed with water, brine, and dried (Na2SO₄). After removalof the solvent, the residue was purified by column chromatography onSiO₂ (3:1 hexanes-EtOAc) to give 120 mg of the desired methylamide.

The above methylamide (110 mg, 0.311 mmol) was dissolved in 3 mL of THFand LiOH (26 mg, 0.62 mmol) was added as a solution in 1 mL water. Themixture was stirred at room temperature overnight. The reaction mixturewas partitioned between CH₂Cl₂ and water, and the water was separatedand adjusted to pH to 3–4 with HCl and extracted again with CH₂Cl₂. Thecombined organic layers were washed with brine, dried (Na₂SO₄) andfiltered. After removal of the solvent, the carboxylic acid was obtainedas a solid which was used in next step without any purification.

To a suspension of the above carboxylic acid (60 mg, 0.185 mmol) in 1.5mL of DMF was added Hunig's base (87 uL, 0.50 mmol). After 5 min, HATU(90.2 mg, 0.23 mmol) and HOAt (5.0 mg, 0.037 mmol) were added followedby N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (51.8mg, 0.190 mmol). The mixture was stirred overnight and was then dilutedwith EtOAc, washed with water, brine, dried (Na₂SO₄) and concentrated invacuo. The crude product was purifed twice by flash columnchromatography (3–5% MeOH in CH₂Cl₂) to give 85 mg of the desiredproduct with some impurities. Final purification by reverse-phase HPLC(water:acetonitrile) gave 45 mg of the title compound.

Example 7 Synthesis of1-methyl-7-(2-morpholin-4-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

A mixture of the 2-methyl-4-chloropyridine (1.00 g, 7.84 mmol), NBS(1.42 g, 8.00 mmol) and benzoyl peroxide (˜10 mg) in 10 mL of CCl₄ washeated at reflux for 5 h. After cooling down, the reaction mixture wasfiltered and filtrate was concentrated to give the crude productsmixture, which was dissolved in DMF and treated with morpholine (1.00mL) and K₂CO₃ (1 g). The mixture was stirred overnight. The mixture wasthen diluted with EtOAc, washed with water, brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The crude product was purified bycolumn chromatography on SiO₂ to give 400 mg of the desired2-morpholinomethyl-4-chloropyridine.

To a solution of the 7-hydroxyindole ester (see Example 6) (473.6 mg,2.16 mmol) in 10 mL of dry DMF was added NaH (86.4 mg of a 60%dispersion in mineral oil, 2.16 mmol), resulting in a deep bluesolution. A solution of the 4-chloropyridine intermediate from above(380 mg, 1.79 mmol) in 3 mL of DMF was added and the mixture was heatedto 140° C. in a sealed tube for 4.5 h. After cooling down, the reactionmixture was diluted with EtOAc, washed with water, brine, dried (Na₂SO₄)and filtered. After removal of solvent, the residue was purified bycolumn chromatography on silica gel eluting with 1–4% MeOH in CH₂Cl₂ togive 240 mg of a mixture of unreacted chloropyridine and the desiredether intermediate, which was used in next step without furtherpurification.

The mixture of the above ether and unreacted chloropyridine wasdissolved in 3 mL of THF and was treated with 1 mL of aqueous LiOH (60mg) solution. The reaction mixture was stirred overnight and then wasconcentrated in vacuo. The residue was diluted with 1 M NaOH andextracted with ether to remove unreacted 7-hydroxyindole ester andchloropyridine. The aqueous layer was then acidified with 2 M HCl to pH4–5 and extracted with CH₂Cl₂ 6 times. The combined organic extractswere dried (Na₂SO₄); filtered and concentrated to give 68 mg of thedesired indole acid.

To a solution of the indole acid (65.0 mg, 0.177 mmol) in 2 mL of DMFwas added Hunig's base (87 uL, 0.50 mmol). After 5 min, HATU (90.2 mg,0.23 mmol) and HOAt (5 mg, 0.037 mmol) were added, and thenN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (49 mg,0.180 mmol). The mixture was stirred overnight. The reaction mixture wasdiluted with EtOAc, washed with water, brine, dried (Na₂SO₄), filteredand concentrated in vacuo. The crude product was purified by preparativeTLC (10% MeOH in DCM) to give 35 mg of product, which was purified byreverse-phase HPLC to give 20 mg of the title compound.

Example 8 Synthesis of7-(2-dimethylaminomethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

A mixture of 4-chloropyridine-2-carboxylic acid (2.00 g, 12.69 mmol),methyl iodide (1.25 mL, 20.0 mmol) and DBU (3.34 mL, 22.0 mmol) in 20 mLof dry acetonitrile was stirred over 2 days. The reaction mixture wasdiluted with ether, washed with water, brine, dried over Na₂SO₄ andconcentrated. The residue was purified by chromatography on silica gelto give 1.6 g of the desired methyl ester.

To a solution of DIBAL in toluene (1 M, 12.3 mL, 12.3 mmol) and THF(1:1) in an ice-salt bath, was added a solution of the above ester (700mg, 4.10 mmol) in 10 mL of THF. After addition, the reaction mixture wasallowed to warm up to room temperature and stir for 3 h. The mixture wasthen poured into crushed ice with 5 mL of 4M NaOH, extracted with EtOAc,dried over Na₂SO₄ and concentrated in vacuo to give 450 mg of thedesired alcohol, which was used in next step without purification.

To a solution of the above alcohol (430 mg, 3.0 mmol) in DMF (10 mL) wasadded NaH (144 mg of a 60% dispersion in mineral oil, 3.60 mmol) and themixture was then cooled in an ice bath. Benzyl bromide (437 uL, 3.60mmol) was then added and the mixture was stirred at room temperature for3 h. After normal aqueous work-up and short column chromatographicpurification, 600 mg of desired benzyl ether was obtained.

A Schlenk tube was charged with Pd(OAc)₂ (16 mg, 0.07 mmol), K₃PO₄ (525mg, 2.40 mmol), di-t-butylbiphenylphosphine (42 mg, 0.14 mmol) and the7-hydroxyindole ester (see Example 6) (307 mg, 1.4 mmol), and cappedwith a septum and purged with argon. A solution of the benzyl ether fromabove (270 mg, 1.16 mmol) in 3 mL of toluene was then added via syringe.The mixture was heated at 100° C. with stirring under argon for 6 h. Thereaction mixture was filtered through a layer of diatomaceous earth andthe solid residue was rinsed with CH₂Cl₂. The combined filtrate wasconcentrated. The crude product was purified by column chromatography togive 61% yield of the desire indole ether.

To a solution of the indole ether (400 mg, 0.96 mmol) in 8 mL THF wasadded a solution of LiOH (120 mg, 2.86 mmol) in 2.5 mL of H₂O. Themixture was stirred overnight, then was diluted with water, acidifiedwith 2 N HCl to pH 4–5, and extracted with CH₂Cl₂. The combined extractswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo togive 360 mg of desired carboxylic acid, which was pure enough for thenext step without purification.

To a solution of the indole carboxylic acid (360 mg, 0.93 mmol) in 4 mLof DMF was added Hunig's base (418 uL, 2.4 mmol). After 5 min, HATU (439mg, 1.12 mmol) and HOAt (12 mg, 0.09 mmol) were added and thenN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (253 mg,0.93 mmol). The mixture was stirred overnight. The reaction mixture wasdiluted with EtOAc, washed with water, brine, dried (Na₂SO₄) andconcentrated in vacuo. The crude product was purified by columnchromatography (1:2 hexanes-EtOAc) to give 390 mg of the desired amide.

To a solution of the amide (390 mg, 0.61 mmol) in 4 mL of HOAc was added2 mL of concentrated HCl and the mixture was heated at 100° C. for 3 h.After cooling down, the reaction mixture was poured into crushed ice,adjusted to pH to 5–6, extracted with EtOAc, washed with saturatedaqueousd NaHCO₃, brine, and dried over Na₂SO₄. After removal of thesolvent, the residue was purified by column chromatography (3–5% MeOH inCH₂Cl₂) to give 180 mg of the desired debenzylated pyridine-methanol.

To a solution of the pyridine-methanol (63 mg, 0.11 mmol) and CBr₄ (76mg, 0.23 mmol) in 2 mL of CH₂Cl₂ was added Ph₃P (36 mg, 0.14 mmol) at 0°C. and the mixture was stirred at 0° C. for 1 h. The reaction mixturewas concentrated in vacuo and the resulting yellow foam was dissolved in2 mL DMF, to which was added 1 mL of 2 M Me₂NH in THF and solid K₂CO₃.The mixture was stirred at room temperature for 3 h. The reactionmixture was diluted with EtOAc, washed with water, brine, dried (Na₂SO₄)and concentrated in vacuo. The crude product was purified by columnchromatography to give 15 mg of the title compound.

Example 9 Synthesis of1-methyl-7-(2-methylamino-pyrimidin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-2-methoxy-3-methylcarbamoyl-phenyl)-amide

To a solution of 7-hydroxyindole ester (see Example 6) (2.10 g, 10 mmol)in DMSO (25 mL) was added t-BuOK solution in THF (1.0 M, 10 mL, 10 mmol)at room temperature. The reaction color changed from red to green.2,4-Dichloropyrimidine (1.50 g, 10 mmol) was then added. The reactionmixture was heated to 70° C. for 3 h. The reaction was cooled, dilutedwith H₂O and extracted with EtOAc. The combined organics were washedwith water and brine, dried over MgSO₄, filtered and concentrated togive a crude solid. The solid was triturated with 30% EtOAc/hexanes andfiltered to give 1.4 g of the desired ether. The filtrate wasconcentrated down and purified by column chromatography on SiO₂ (15%–40%EtOAc/hexanes eluent) to give an additional 1.2 g of the etherintermediate as a white solid, for a combined yield of 2.6 g (78%).

To a solution of the above chloro-pyrimidinyl ether (1.00 g, 3.01 mmol)in 15 mL anhydrous THF in a sealed tube was added 6.0 eq of MeNH₂solution in THF. The reaction was heated at 70° C. overnight. It wasthen cooled down to room temperature, diluted with water and extractedwith EtOAc. The organics were washed with brine, dried, filtered andconcentrated to give a foam, which was purified by flash columnchromatography on SiO₂ (20%–50% EtOAc/hexanes eluent) to give 812 mg ofdesired methylamino-pyrimidine intermediate.

To a solution of the above intermediate (812 mg, 2.49 mmol) in MeOH/THF(15 mL/15 mL) was added LiOH as an aqueous solution (313 mg in 2 mL ofH₂O). The reaction color changed to light green. The reaction wassitrred at room temperature for 6 h, then concentrated in vacuo. Waterwas added, the mixture was washed with Et₂O and the organic layer wasdiscarded. The aqueous phase was acidified to pH 3–4 with 3N HCl andextracted with EtOAc. The combined organic extracts were dried, filtered(MgSO₄) and concentrated down to give 580 mg of the indole carboxylicacid as a pale pink solid.

To a solution of the above indole carboxylic acid (122 mg, 0.41 mmol) inDMF were added HATU (141 mg, 0.37 mmol), TEA (104 uL, 0.74 mmol) andHOAt (25 mg, 0.19 mmol). After 10 min, the aniline intermediate (88 mg,0.37 mmol) was added in one portion. The mixture was stirred at roomtemperature for 8 h. The reaction was then diluted with EtOAc and washedwith water. Most starting aniline was removed by washing with 0.5 Naqueous HCl. The resulting organics were dried (MgSO₄), filtered andconcentrated to give an oil which was purified by column chromatographyon SiO₂ (3%–10% MeOH/CH₂Cl₂ eluents) followed by preparative TLC to give110 mg of the title compound.

Example 10 Synthesis of1-methyl-7-[2-(2-morpholin-4-yl-ethyl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

To a suspension in EtOH (3 mL) of the olefin illustrated above (200 mg,0.364 mmol) was added morpholine (65 μL, 0.75 mmol) and acetic acid (35μL, 0.61 mmol). The mixture was heated to 80° C. under nitrogen for 4 h,after which time a homogeneous solution was obtained. The reaction wasdiluted with dichloromethane (10 mL) and stirred over anhydrous K₂CO₃for 30 min. The solution was then filtered and concentrated. Triturationof the residue with Et₂O provided the product (221 mg, 95%) as a tanpowder.

Example 11 Synthesis of1-methyl-7-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yloxy]-1H-indole-2-carboxylicacid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amide

To a suspension of the indole carboxylic acid (2.10 g, 7.47 mmol) indichloromethane (40 mL) was added oxalyl chloride (6.0 mL of a 2.0 Msolution in dichloromethane, 12 mmol) and DMF (10 μL) under anatmosphere of dry N₂. After stirring at ambient temperature for 1.5 h,the resulting yellow solution was concentrated in vacuo to provide thecrude acid chloride as a yellow powder. This material was dissolved inTHF (50 mL), and to this solution was addedN-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (2.13 g,7.50 mmol), pyridine (971 μL, 12.0 mmol) and DMAP (50 mg). The reactionwas stirred at ambient temperature for 4 days, then taken up indichloromethane (300 mL), washed with saturated NaHCO₃ (40 mL), andconcentrated in vacuo. The resulting solids were triturated with etherto provide the product (2.94 g, 72%) as an analytically pure whitepowder. O-de-benzylation and further transformation to the titlecompound were performed as previously described (Example 1) to affordthe title compound.

Example 12 Synthesis ofN-[3-amino-2-methoxy-5-(1-methylcyclopropyl)-phenyl]-methanesulfonamide

To a solution of 4-hydroxyacetophenone (10.0 g, 73.5 mmol) in DMF (74mL) was added imidazole (12.0 g, 176.3 mmol) and tert-butyldimethylsilylchloride (13.3 g, 88.1 mmol). The colorless solution was stirred for0.75 h at room temperature then quenched with saturated aqueous NaHCO₃.The aqueous phase was extracted with hexanes and the combined organiclayers were washed with saturated aqueous NaHCO₃. The organic layerswere dried over sodium sulfate, filtered, and concentrated to providethe silyl ether (18.0 g, 98%) as a white solid which was utilizedwithout further purification.

Methyl(triphenylphosphonium)bromide (17.1 g, 48.0 mmol) was suspended inTHF (96 mL) and cooled to 0° C. n-Butyllithium (2.5 M in hexane, 19.2mL, 48.0 mmol) was added dropwise to the mixture. The red solution wasstirred at room temperature for 0.5 h. The acetophenone silyl ether(10.0 g, 40.0 mmol) from above was added. The solution turned brightyellow and a white precipitate formed. The mixture was stirred for 1 hat room temperature and then the solution was quenched with saturatedaqueous NaHCO₃. The aqueous phase was extracted with diethyl ether andthe combined organic layers were washed with saturated aqueous NaHCO₃.The organic layers were dried over sodium sulfate, filtered andconcentrated. The resulting mixture was eluted through a plug of silicagel (hexanes) and the filtrate was concentrated to provide the styrene(8.36 g, 84%) as a colorless oil.

Diethylzinc (1.0 M in hexanes, 69 mL, 69 mmol) was added to a solutionof the above styrene intermediate (6.85 g, 27.6 mmol) in dichloroethaneat 0° C. Diiodomethane (11.2 mL, 138 mmol) was then added dropwise tothe solution and the resulting mixture was stirred at 0° C. for 0.5 hand allowed to warm to room temperature for 2 h. The opaque mixture wasquenched with saturated aqueous NH₄Cl. The aqueous phase was extractedwith methylene chloride and the combined organic layers were washed withsaturated aqueous NaHCO₃. The organic layers were dried over sodiumsulfate, filtered through diatomaceous earth, and concentrated. Thecrude residue was dissolved in THF (50 mL) and TBAF (1.0 M in THF, 28mL, 28 mmol) was added at room temperature. The solution was stirred for2 h and then quenched with aqueous 1.0 M HCl. The aqueous phase wasextracted with EtOAc and the combined organic layers were washed withsaturated aqueous NaHCO₃. The organic layers were dried over sodiumsulfate, filtered and concentrated. Purification by silica-gelchromatography (1% 2-propanol/12% EtOAc in hexanes) provided the phenol(2.77 g, 68%) as a white solid: (NO)18-crown-6•H(NO₃)₂ ¹ (18.0 g, 43.0mmol) was added to a solution of phenol (2.77 g, 18.7 mmol) in EtOAc.The reaction mixture was heated to reflux for 5 min and then cooled toroom temperature. The mixture was poured onto aqueous 1.0 M HCl. Theaqueous phase was extracted with diethyl ether. The combined organiclayers were dried over sodium sulfate, filtered and concentrated. Theresidue was dissolved in acetonitrile/MeOH (9:1, 62 mL), cooled to 0° C.and N,N-diisopropylethylamine (13 mL, 74.8 mmol) was added slowly. Thedeep red solution was warmed to room temperature andtrimethylsilyldiazomethane (2.0 M in hexane, 18.7 mL, 37.4 mmol) wasadded slowly to control nitrogen evolution. After stirring at roomtemperature for 0.5 h, the mixture was concentrated and partitionedbetween methylene chloride and saturated aqueous NH₄Cl. The aqueouslayer was extracted with methylene chloride and the combined extractswere dried over sodium sulfate, filtered and concentrated. Purificationby silica-gel chromatography (6% EtOAc in hexanes) provided thedinitroanisole (2.21 g, 47%) as a red oil.

Tin(II)chloride dihydrate (11.9 g, 52.6 mmol) was added to a solution ofthe above dinitroanisole (2.21 g, 8.76 mmol) in EtOAc (30 mL). Themixture was heated to reflux for 0.25 h upon which the solution becamered in color. The solution was cooled to room temperature and pouredonto aqueous 2.0 M NaOH. The aqueous phase was extracted with EtOAc andthe combined organic layers were washed with saturated aqueous NaHCO₃.The organic layers were dried over sodium sulfate, eluted through a plugof silica gel (1% ammonium hydroxide in methylene chloride), and thefiltrate was concentrated. The residue was dissolved in diethyl etherand extracted (3×) with 1.0 M HCl. The pH of the combined aqueous layerswas adjusted to pH=12 with 2.0M NaOH and extracted with methylenechloride. The combined organic layers were dried over sodium sulfate,filtered and concentrated to provide diaminoanisole (860 mg, 52%) as ared oil.

Triethylamine (521 μL, 3.74 mmol) was added to a solution of the abovediaminoanisole (718 mg, 3.74 mmol) in methylene chloride at −10° C.Methanesulfonyl chloride (290 μL, 3.74 mmol) was then added dropwiseover a 10 min period and the resulting solution was allowed to slowlywarm to room temperature over 2 h. The mixture was quenched withsaturated aqueous NaHCO₃ and the aqueous layer was extracted withmethylene chloride. The combined organic layers were dried over sodiumsulfate, filtered and concentrated. Purification by silica gelchromatography (1% ammonium hydroxide/35% EtOAc in hexanes to 1%ammonium hydroxide/50% EtOAc in hexanes) provided a red solid which wastriturated with a diethyl ether/hexanes (1:1) to yield the titlecompound (510 mg, 51%) as a pale brown solid, mp 144–146° C.

This intermediate can then be coupled to the indole core and reactedfurther by the procedures described in the examples above, to formdesired analogous indole amides.

For example, the product of Example 12 was used to prepare the followingcompound:

Example 13 Synthesis of 7-mercapto-1-methyl-1H-indole-2-carboxylic acidethyl ester

7-Hydroxy-1-methylindole-2-carboxylic acid ethyl ester (1.06 g; 0.005mol) was dissolved in 8 mL DMF in a 3-neck round bottom flask undernitrogen purge. Diazabicyclo[2.2.2.]octane (DABCO) (1.12 g, 0.010 mol)and Me₂NC(═S)Cl (1.236 g, 0.010 mol) were added sequentially, each in asingle portion,. The mixture was left stirring at room temperatureovernight. A suspension formed. The reaction mixture was poured ontowater and extracted 3× with EtOAc. The combined organic layers werewashed 3× with water, then brine, then dried over MgSO₄, concentrated toa semi-solid, ca 1.6 g.

The above residue was taken up in hot i-PrOH (about 30 mL) and treatedwith charcoal. The solution was cooled overnight in a freezer, then theresulting beige solid was filtered off and washed with cold i-PrOH, thenpetroleum ether providing the desired thiocarbamate (0.92 g).

The above thiocarbamate (31 mg; 0.0001 mol) was added into a pressuretube, along with Me₂NPh (0.63 mL; 0.005 mol) and a magnetic stir bar.The tube was heated in a microwave oven to 250° C. for 10 min. Thereaction mixture was then poured onto 4 N aqueous HCl and the gummyprecipitate was extracted with EtOAc. The solution was allowed toevaporate providing the desired isomerized intermediate.

The resulting intermediate can be hydrolyzed to form the desired thiol,which can then be further reacted by the methods described above for theanalogous 7-hydroxyindole intermediate to form the desired thioetherderivatives.

For example, the following compound may be prepared from the above thiolusing the methods described in the above examples:

Example 14 Synthesis of 7-hydroxy-benzo[b]thiophene-2-carboxylic acidmethyl ester

To a 150 mL heating flask was added 1 g (5.52 mmol) of3-methoxy-2-nitro-benzaldehyde, 0.5 mL (5.7 mmol) of mercapto-aceticacid methyl ester, 1.8 g (13 mmol) of potassium carbonate and 50 mL ofanhydrous DMF. The opaque, gold solution was stirred overnight at 60° C.in a sealed tube. After 14 h the reaction was poured into 200 mL ofwater, stirred 2 h, and extracted with EtOAc to provide 1 g (81%) of thedesired intermediate, which was used without further purification.

Dissolved 1 g (4.5 mmol) of the above intermediate in about 50 mL CH₂Cl₂in a 500 mL 3-neck round-bottom flask under nitrogen purge and cooled inan ice/acetone bath. Placed the BBr₃/CH₂Cl₂ solution (3 eq) in additionfunnel, and added dropwise at such a rate that the temperature wasmaintained <5° C. throughout. Allowed to warm to room temperature andcontinued stirring overnight. The reaction was cooled back down in anice/acetone bath and added 50 mL MeOH dropwise; initially very slowly,since it was exothermic. After the addition of MeOH was complete, thereaction was allowed to warm to room temperature and then concentratedin vacuo to obtain the title compound (900 mg, 93%).

The 7-hydroxybenzothiophene intermediate can then be reacted further asdescribed in Examples above for 7-hydroxyindole to produce compounds offormula I

Example 15 Synthesis of1-methyl-7-(2-pyrrolidin-1-ylmethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide

To a suspension of 4-chloropyridine-2-carboxylic acid (4.5 g, 29.0 mmol)in methylene chloride (120 mL) was added oxalyl chloride (3.0 mL, 1.2eq) under Ar₂. The reaction was cooled to 0° C., added 500 uL of DMF. Alarge amount of gas was generated in situ. The reaction was stirred atroom temperature for 1.5 h then concentrated. Dry MeOH (50 mL) was addedto the crude acyl chloride residue. The reaction was stirred at roomtemperature for 0.5 h then quenched with NaHCO₃ (5%) to neutral,extracted with EtOAc, and washed with brine. The combined organics weredried over MgSO₄, filtered and concentrated in vacuo to give 5.0 g ofcrude solid which was triturated with 5% EtOAc/hexane to give thedesired intermediate methyl ester as a light yellow solid (4.5 g, 90%).

To a solution of the above methyl ester (2.5 g, 14.6 mmol) in 100 mL ofdry THF at −78° C. was added diisobutylaluminum hydride dropwise (1.0 Min THF, 29.1 mmol) and the reaction mixture was stirred at thattemperature under Ar₂ for 2 h. The reaction was quenched with MeOH at−78° C. and then sodium potassium tartrate solution (˜1.0 M, 180 mL) wasadded and the mixture was stirred and warmed up to room temperature over1 h. The slurry was diluted with EtOAc (60 mL) and the organic layer wasseparated and washed with brine and dried with sodium sulfate. Thesolvent was removed under mild vacuum at room temperature (volatilecompound) to give the desired aldehyde (1.87 g, 91%) which solidified asa light yellow crystal by standing at room temperature.

To a solution of the above aldehyde (1.6 g, 11.3 mmol) in 50 mL of MeOH(dry) was added TsOH.H₂O (363 mg, 0.17 eq) and (MeO)₃CH (5 mL). Thereaction was heated up to reflux for 2 h then partitioned between EtOAcand water. The organic phase was then washed with NaHCO₃ solution andbrine. The combined organics were dried over MgSO₄, filtered andconcentrated in vacuo to give the desired4-chloro-2-dimethoxymethyl-pyridine as a light yellow oil (1.83 g, 86%).

A sealed tube was charged with Pd(OAc)₂ (57.47 mg, 0.06 eq), K₃PO₄(1.904 g, 2.0 eq), di-tert butyl phosphine biphenyl (152.7 mg, 0.12 eq)and 7-hydroxy-methylindole-2-carboxylic acid methyl ester (934.8 mg,4.26 mmol) and toluene (20 mL), and capped with a septum. The system wasdegased and charged with argon, repeated for a couple of times. Then asolution of the 4-chloro-2-dimethoxymethyl-pyridine (800 mg, 4.26 mmol)from above in 4 mL of toluene was added via syringe. The mixture washeated at 100° C. with stirring under argon for 3 h. The reaction wascooled to room temperature, and the reaction mixture was filteredthrough a pad of diatomaceous earth and rinsed with methylene chloride.The combined filtrates were concentrated in vacuo. The crude productswere purified by silica gel chromatography (30%–70% EtOAc/hex) to givethe desired ether (790 mg, 50%) as a brown oil.

To a solution of the above ether (770 mg, 2.1 mmol) in THF/MeOH (25mL/10 mL) was added LiOH.H₂O (218.1 mg, 2.50 eq) dissolved in 3 mL ofwater. The clear reaction solution was stirred at room temperature for 5h, then concentrated in vacuo. The residual aqueous solution was dilutedwith water (15 mL), and extracted with ether. The organic layer wasdisgarded. The aqueous layer was acidified to pH 5 with 1.4 N HCl (˜2.5mL). A large amount of white precipitates were extracted with 200 mL ofEtOAc and washed with brine. The combined organics were dried overMgSO₄, filtered and concentrated in vacuo to give the desiredindole-2-carboxylic acid intermediate (644 mg, 90.5%) as a white foam.

To a solution of the above carboxylic acid (651 mg, 1.9 mmol) in DMF (20mL) were added HATU (723.2 mg, 1.0 eq) diisopropylethylamine (662.6 uL,2.0 eq) and HOAt (129.4 mg, 0.5 eq). After 10 min,N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide was addedin one portion. After stirring at room temperature overnight, thereaction was worked up with EtOAc, washed with water and brine. Thecombined organics were dried over MgSO₄, filtered and concentrated invacuo to give an oil which was purified by silica gel Chromatography(50% EtOAc/hexanes) to give the desired amide (1.03 g, 91%) as a whitefoam.

To a solution of the above amide (1.08 g, 1.81 mmol) in acetonitrile andwater (20 mL/20 mL) was added CBr₄ (905 mg, 2.0 eq). The reaction wasrefluxed (oil bath temperature: 80° C.) overnight. The reaction wascooled to room temperature, adjusted to pH 7 with NaHCO₃ solution,extracted with EtOAc until no desired product was left in the aqueouslayer. The combined organics were dried over MgSO₄, filtered andconcentrated to give 1.5 g (>100%) of a light brown colored foam whichwas purified by silica gel chromatography (20%–70% EtOAc/hexanes) toprovide the desired aldehyde intermediate as a yellow foam.

To a solution of the above aldehyde (80 mg, 0.145 mmol) indichloroethane (10 mL) were added glacial HOAc (273 uL) and pyrrolidine(375 uL). The reaction was stirred at room temperature for 20 min. Thereaction solution became cloudy. Triacetoxyborohydride (245 mg) wasadded to the reaction mixture. The reaction was stirred at roomtemperature for 1 h, then NaHCO₃ (saturated solution) was added, themixture stirred for 10 min, then extracted with methylene chloride. Thecombined organics were washed with brine, dried over MgSO₄, filtered andconcentrated down to give 85 mg of foam which was >97% pure by HPLC and1HNMR. The foam was further purified by silica gel chromatography (5%–8%MeOH/methylene chloride) to provide the title compound (75 mg, 85%).

Example 16 Synthesis of1-methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-2-methoxy-phenyl)-amide

To a solution of 1-methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-[1,3]dioxolan-2-yl-2-methoxy-phenyl)-amide (0.20 g,0.40 mmol) in THF (3.00 mL) was added 2.0 N HCl (2 mL). The solution wasallowed to stir at room temperature and under an ambient atmosphere for17.5 h. The solution was diluted in EtOAc (20 mL) and transferred to aseparatory funnel. The aqueous layer was separated and the organic layerwas washed with saturated NaHCO₃ solution (2×10 mL), water (1×10 mL),brine (1×10 mL), dried over MgSO₄, filtered and the solvent wasevaporated to give the desired aldehyde as a yellow foam (0.16 g, 90%).

To a solution of the above aldehyde (0.04 g, 0.09 mmol) indichloroethane (2.00 mL) was added acetic acid (0.06 mL, 1.06 mmol)followed by the dropwise addition of N,N,N′-trimethylethylenediamine(0.28 mL, 2.18 mmol) at 0° C. The solution was allowed to warm to roomtemperature and was stirred for 30 min., followed by the batchwiseaddition of sodium triacetoxyborohydride (0.05 g, 0.22 mmol). Thereaction was allowed to stir for 17.5 h under an ambient atmosphere andat room temperature. The solution was diluted with EtOAc (10 mL) andquenched with 3% NH₄OH (1 mL). The biphasic system was transferred to aseparatory funnel and the aqueous layer was separated. The organic layerwas washed with 3% NH₄OH (2×2.0 mL), water (2×10 mL), brine (2×10 mL),dried over MgSO₄, filtered and the solvent was evaporated. The resultingresidue was dissolved in CH₂Cl₂ and flash chromatographed (7%MeOH/CH₂Cl₂, 0.5% NH₄OH) to give the crude product as a yellow oil. Thematerial was again flash chromatographed (8% MeOH/CH₂Cl₂, 0.5% NH₄OH) togive the title compound as a colorless foam (0.02 g, 41%).

Method of Use

In accordance with the invention, there are provided novel methods ofusing the compounds of the formula (I). The compounds disclosed thereineffectively block inflammatory cytokine production from cells. Theinhibition of cytokine production is an attractive means for preventingand treating a variety of cytokine mediated diseases or conditionsassociated with excess cytokine production, e.g., diseases andpathological conditions involving inflammation. Thus, the compounds areuseful for the treatment of diseases and conditions as described in theBackground section, including the following conditions and diseases:

-   osteoarthritis, atherosclerosis, contact dermatitis, bone resorption    diseases, reperfusion injury, asthma, multiple sclerosis,    Guillain-Barre syndrome, Crohn's disease, ulcerative colitis,    psoriasis, graft versus host disease, systemic lupus erythematosus    and insulin-dependent diabetes mellitus, rheumatoid arthritis, toxic    shock syndrome, Alzheimer's disease, diabetes, inflammatory bowel    diseases, acute and chronic pain as well as symptoms of inflammation    and cardiovascular disease, stroke, myocardial infarction, alone or    following thrombolytic therapy, thermal injury, adult respiratory    distress syndrome (ARDS), multiple organ injury secondary to trauma,    acute glomerulonephritis, dermatoses with acute inflammatory    components, acute purulent meningitis or other central nervous    system disorders, syndromes associated with hemodialysis,    leukopherisis, granulocyte transfusion associated syndromes, and    necrotizing entrerocolitis, complications including restenosis    following percutaneous transluminal coronary angioplasty, traumatic    arthritis, sepsis, chronic obstructive pulmonary disease and    congestive heart failure. The compounds of the invention may also be    useful for anticoagulant or fibrinolytic therapy (and the diseases    or conditions related to such therapy) as described in U.S.    application Ser. No. 10/630,599 and PCT/US03/23841.

The compounds of the invention are also p38 MAP kinase inhibitors.Methods for screening p38 MAP kinase inhibitors are known in the art. Asdisclosed in the Background of the Invention, the compounds of theinvention will therefore be useful for treating oncological diseases.These diseases include but are not limited to solid tumors, such ascancers of the breast, respiratory tract, brain, reproductive organs,digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma and mesothelioma.

Examples of brain cancers include, but are not limited to brain stem,optic and hypophtalmic glioma, cerebella and cerebral astrocytoma,medulloblastoma, ependymoma, as well as pituitary,neuroectodermal andpineal tumor.

Examples of peripheral nervous system tumors include, but are notlimited to neuroblastoma, ganglioneuroblastoma, and peripheral nervesheath tumors.

Examples of tumors of the endocrine and exocrine system include, but arenot limited to thyroid carcinoma, adrenocortical carcinoma,pheochromocytoma, and carcinoid tumors.

Tumors of the male reproductive organs include, but are not limited toprostate and testicular cancer.

Tumors of the female reproductive organs include, but are not limited toendometrial, cervical, ovarian, vaginal, and vulvar cancer, as well assarcoma of the uterus.

Tumors of the digestive tract include, but are not limited to anal,colon, colorectal, esophageal, gallblader, gastric, pancreatic, rectal,small-intestine, and salivary gland cancers.

Tumors of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, and urethral cancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma.

Examples of liver cancers include, but are not limited to hepatocellularcarcinoma (liver cell carcinomas with or without fibrolamellar variant),hepatoblastoma, cholangiocarcinoma (intrahepatic bile duct carcinoma),and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited tolaryngeal/hypopharyngeal/nasopharyngeal/oropharyngeal cancer, and lipand oral cavity cancer.

Lymphomas include, but are not limited to AIDS-related lymphoma,non-Hodgkin's lymphoma, Hodgkins lymphoma, cutaneous T-cell lymphoma,and lymphoma of the central nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, Ewings sarcoma, malignant fibrous histiocytoma,lymphosarcoma, angiosarcoma, and rhabdomyosarcoma. Leukemias include,but are not limited to acute myeloid leukemia, acute lymphoblasticleukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia,and hairy cell leukemia.

Plasma cell dyscrasias include, but are not limited to multiple myeloma,and Waldenstrom's macroglobulinemia.

These disorders have been well characterized in man, but also exist witha similar etiology in other mammals, and can be treated bypharmaceutical compositions of the present invention.

For therapeutic use, the compounds may be administered in anyconventional dosage form in any conventional manner. Routes ofadministration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous.

The compounds may be administered alone or in combination with adjuvantsthat enhance stability of the inhibitors, facilitate administration ofpharmaceutic compositions containing them in certain embodiments,provide increased dissolution or dispersion, increase inhibitoryactivity, provide adjunct therapy, and the like, including other activeingredients. Advantageously, such combination therapies utilize lowerdosages of the conventional therapeutics, thus avoiding possibletoxicity and adverse side effects incurred when those agents are used asmonotherapies. The above described compounds may be physically combinedwith the conventional therapeutics or other adjuvants into a singlepharmaceutical composition. Reference is this regard may be made toCappola et al.: U.S. patent application Ser. No. 09/902,822, PCT/US01/21860 and U.S. application Ser. No. 10/214,782, each incorporated byreference herein in their entirety. Advantageously, the compounds maythen be administered together in a single dosage form. In someembodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 5%, but more preferablyat least about 20%, of a compound of formula (I) (w/w) or a combinationthereof. The optimum percentage (w/w) of a compound of the invention mayvary and is within the purview of those skilled in the art.Alternatively, the compounds may be administered separately (eitherserially or in parallel). Separate dosing allows for greater flexibilityin the dosing regime.

As mentioned above, dosage forms of the compounds described hereininclude pharmaceutically acceptable carriers and adjuvants known tothose of ordinary skill in the art. These carriers and adjuvantsinclude, for example, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 1–1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. Referencein this regard may also be made to U.S. application Ser. No. 10/313,667.As the skilled artisan will appreciate, lower or higher doses may berequired depending on particular factors. For instance, specific dosageand treatment regimens will depend on factors such as the patient'sgeneral health profile, the severity and course of the patient'sdisorder or disposition thereto, and the judgment of the treatingphysician.

Biological Assays

Inhibition of TNF Production in THP Cells

The inhibition of cytokine production can be observed by measuringinhibition of TNFα in lipopolysaccharide stimulated THP cells (forexample, see W. Prichett et al., 1995, J. Inflammation, 45, 97). Allcells and reagents were diluted in RPMI 1640 with phenol red andL-glutamine, supplemented with additional L-glutamine (total: 4 mM),penicillin and streptomycin (50 units/ml each) and fetal bovine serum(FBS, 3%) (GIBCO, all conc. final). Assay was performed under sterileconditions; only test compound preparation was nonsterile. Initial stocksolutions were made in DMSO followed by dilution into RPMI 1640 2-foldhigher than the desired final assay concentration. Confluent THP.1 cells(2×10⁶ cells/ml, final conc.; American Type Culture Company, Rockville,Md.) were added to 96 well polypropylene round bottomed culture plates(Costar 3790; sterile) containing 125 μl test compound (2 foldconcentrated) or DMSO vehicle (controls, blanks). DMSO concentration didnot exceed 0.2% final. Cell mixture was allowed to preincubate for 30min, 37° C., 5% CO₂ prior to stimulation with lipopolysaccharide (LPS; 1μg/ml final; Siga L-2630, from E.coli serotype 0111.B4; stored as 1mg/ml stock in endotoxin screened distilled H₂O at −80° C.). Blanks(unstimulated) received H₂O vehicle; final incubation volume was 250 μl.Overnight incubation (18–24 hr) proceeded as described above. Assay wasterminated by centrifuging plates 5 min, room temperature, 1600 rpm(400×g); supernatants were transferred to clean 96 well plates andstored −80° C. until analyzed for human TNFα by a commercially availableELISA kit (Biosource #KHC3015, Camarillo, Calif.). Data was analyzed bynon-linear regression (Hill equation) to generate a dose response curveusing SAS Software System (SAS institute, Inc., Cary, N.C.). Thecalculated IC₅₀ value is the concentration of the test compound thatcaused a 50% decrease in the maximal TNFα production.

Preferred compounds have an IC₅₀<1 uM in this assay.

Inhibition of Other Cytokines

By similar methods using peripheral blood monocytic cells, appropriatestimuli, and commercially available ELISA kits (or other method ofdetection such as radioimmunoassay), for a particular cytokine,inhibition of IL-1beta, GM-CSF, IL-6 and IL-8 can be demonstrated forpreferred compounds (for example, see J. C. Lee et al., 1988, Int. J.Immunopharmacol., 10, 835).

All publications, patent publications and patent applications cited inthis application are incorporated herein by reference in their entirety.

1. A compound of the formula (I)

wherein: Ar¹ is chosen from phenyl, naphthyl, tetrahydronaphthyl,indanyl and indenyl, each Ar¹ is optionally substituted with one R¹, andwherein Ar¹ is independently substituted with two R² groups; R¹ ishalogen, NO₂, NH₂, J-N(R^(a))—(CH₂)_(m)—, N(J)₂—(CH₂)_(m)—, NH₂C(O)—,J-N(R^(a))—C(O)—, J-S(O)_(m)—N(R^(a))—, J-N(R^(a))—S(O)_(m)—; Q isCR^(p); Y is —N(R^(x))—; wherein R^(a), R^(p), R^(v), R^(x) and R^(y)are each independently hydrogen or C₁₋₅ alkyl; X is —CH₂—, —N(R^(a))—,—O— or —S—; W is CH; each m is independently 0,1 or 2; J is C1–10 alkyloptionally substituted by R^(b); R² is chosen from C1–6 alkyl, C3–7cycloalkyl optionally substituted by C1–5 alkyl, C1–4 acyl, aroyl, C1–4alkoxy, each being optionally partially or fully halogenated, halogen,C1–6 alkoxycarbonyl, carbocyclesulfonyl and —SO₂—CF₃; each R³, R⁴ and R⁵are independently chosen from hydrogen, C1–6 alkyl and halogen; R⁶ isoptionally attached at a position ortho or meta to the N atom of theindicated ring, and is chosen from a bond, —O—, —O—(CH₂)₁₋₅—, >C(O),—NH—, —C(O)—NH—, —S—, C₁₋₅ alkyl branched or unbranched, C₂₋₅ alkenyl,C₁₋₃ acyl, C₁₋₃ alkyl(OH), aryl each alkyl, alkenyl, acyl and aryl areoptionally substituted by one to three hydroxy, oxo, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₅ alkoxycarbonyl, —NR₇R₈ or NR₇R₈—C(O)—; wherein each R₆ isfurther optionally covalently attached to groups chosen from: hydrogen,—NR₇R₈, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl, hydroxy, C₁₋₃ alkoxy,phenoxy, benzyloxy, arylC₀₋₄ alkyl, each aryl group is optionallysubstituted by one to three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅alkoxycarbonyl, NR₇R₈—C(O)— or C₁₋₄ acyl; each R₇ and R₈ areindependently hydrogen, phenylC₀₋₃alkyl optionally subtituted byhalogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino, or R₇ and R₈ are C₁₋₂ acyl,benzoyl or C₁₋₅ branched or unbranched alkyl optionally substituted byC₁₋₄ alkoxy, hydroxy or mono or diC₁₋₃ alkyl amino; and R^(b) is chosenfrom hydrogen, C1–5 alkyl, hydroxyC1–5 alkyl, C2–5 alkenyl, C2–5alkynyl, carbocycle, C1–5 alkoxy, C1–5 alkylthio, amino, C1–5alkylamino, C1–5 dialkylamino, C1–5 acyl, C1–5 alkoxycarbonyl, C1–5acyloxy, C1–5 acylamino, each of the aforementioned are optionallypartially or fully halogenated, or R^(b) is chosen from C1–5alkylsulphonylamino, hydroxy, oxo, halogen, nitro and nitrile; or thepharmaceutically acceptable salts, acids or isomers thereof.
 2. Thecompound according to claim 1 and wherein: Y is —NH—, —N(CH₂CH₃)— or—N(CH₃)—; X is —N(R^(a))—, or —O—; Q is CH; R₂ is independently chosenfrom C1–6 alkyl, C3–6 cycloalkyl optionally substituted by C1–3 alkyl,acetyl, aroyl, C1–5 alkoxy, each being optionally partially or fullyhalogenated, halogen, methoxycarbonyl, phenylsulfonyl and —SO₂—CF₃; eachR³, R⁴ and R⁵ are hydrogen; R^(b) is chosen from hydrogen, C1–5 alkyl,C2–5 alkenyl, C2–5 alkynyl, C3–8 cycloalkylC0–2 alkyl, aryl, C1–5alkoxy, C1–5 alkylthio, amino, C1–5 alkylamino, C1–5 dialkylamino, C1–5acyl, C1–5 alkoxycarbonyl, C1–5 acyloxy, C1–5 acylamino, C1–5sulphonylamino, hydroxy, halogen, trifluoromethyl, nitro and nitrile. 3.The compound according to claim 2 and wherein: Ar¹ is chosen fromphenyl, naphthyl, tetrahydronaphthyl, indanyl and indenyl, each Ar¹ isoptionally substituted with one R¹, and independently substituted withtwo R² groups; Y is —N(CH₃)—; R⁶ is present, and is chosen from a bond,—O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkyl branched or unbranched,C₂₋₅ alkenyl, C₁₋₃ alkyl(OH) or aryl chosen from phenyl and naphthyl,each alkyl, alkenyl and aryl are optionally substituted by one to threehydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl amino, amino orC₁₋₅ alkoxycarbonyl; wherein each R₆ is further optionally covalentlyattached to groups chosen from: hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆cycloalkylC₀₋₂alkyl, hydroxy, C₁₋₃ alkoxy, phenoxy, benzyloxy,phenylC₀₋₄ alkyl, each phenyl group is optionally substituted by one tothree hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl,—NR₇R₈, NR₇R₈—C(O)— or C₁₋₄ acyl; each R₇ and R₈ are independentlyhydrogen, phenylC₀₋₃alkyl optionally subtituted by halogen, C₁₋₃ alkylor diC₁₋₅ alkyl amino, or R₇ and R₈ are C₁₋₂ acyl, benzoyl or C₁₋₅branched or unbranched alkyl optionally substituted by C₁₋₄ alkoxy,hydroxy or mono or diC₁₋₃ alkyl amino.
 4. The compound according toclaim 3 and wherein: X is —O—; R² is independently chosen from C1–6alkyl, C3–6 cycloalkyl optionally substituted by C1–3 alkyl and C1–5alkoxy, each being optionally be partially or fully halogenated; R⁶ ischosen from a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkylbranched or unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), and phenyl, eachphenyl is optionally substituted by one to three hydroxy, C₁₋₃ alkyl,C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl amino, amino or C₁₋₅ alkoxycarbonyl;wherein each R₆ is further optionally covalently attached to groupschosen from: hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆ cycloalkylC₀₋₂alkyl,benzyloxy, phenylC₀₋₄ alkyl, each above-listed phenyl group isoptionally substituted by one to three hydroxy, oxo, C₁₋₄ alkyl, C₁₋₃alkoxy, C₁₋₅ alkoxycarbonyl, amino, NR₇R₈—C(O)— or C₁₋₄ acyl; each R₇and R₈ are independently hydrogen, phenylC₀₋₂alkyl optionallysubstituted by halogen, C₁₋₃ alkyl or diC₁₋₅ alkyl amino, or R₇ and R₈are C₁₋₅ branched or unbranched alkyl optionally substituted by C₁₋₄alkoxy, hydroxy or mono or diC₁₋₃ alkyl amino; R^(b) is chosen fromhydrogen, C1–5 alkyl, C3–7 cycloalkylC0–2 alkyl, aryl, C1–5 alkoxy,amino, C1–5 alkylamino, C1–3 dialkylamino, C1–3 acyl, C1–5alkoxycarbonyl, C1–3 acyloxy, C1–3 acylamino, C1–3 sulphonylamino,hydroxy, halogen, trifluoromethyl, nitro and nitrile.
 5. The compoundaccording to claim 4 and wherein: Ar¹ is formula (A) or (B)

wherein: when Ar¹ is formula (A) then: R¹ is NH₂, J-N(R^(a))—(CH₂)_(m)—,NH₂C(O)—, J-N(R^(a))—C(O)—, J-S(O)₂— N(R^(a))—, or J-N(R^(a))—S(O)₂— andJ is C₁₋₅ alkyl optionally substituted by R^(b); or when Ar¹ is formula(B) then: R¹ is hydrogen or halogen; R₂ is independently chosen fromC1–5 alkyl, C3–6 cycloalkyl optionally substituted by C1–3 alkyl andC1–5 alkoxy, each being optionally partially or fully halogenated; R⁶ ischosen from a bond, —O—, —O—(CH₂)₁₋₅—, —NH—, —C(O)—NH—, C₁₋₅ alkylbranched or unbranched, C₂₋₅ alkenyl, C₁₋₃ alkyl(OH), and phenyl, eachalkyl, alkenyl and phenyl are optionally substituted by one to threehydroxy, C₁₋₃ alkyl, C₁₋₃ alkoxy, mono or diC₁₋₃ alkyl amino, amino orC₁₋₅ alkoxycarbonyl; wherein each R⁶ is further optionally covalentlyattached to groups chosen from: hydrogen, —NR₇R₈, C₁₋₃ alkyl, C₃₋₆cycloalkylC₀₋₂alkyl, benzyloxy, phenylC₀₋₄ alkyl, each above-listed andphenyl group is optionally substituted by one to three hydroxy, oxo,C₁₋₄ alkyl, C₁₋₃ alkoxy, C₁₋₅ alkoxycarbonyl, amino, NR₇R₈—C(O)— or C₁₋₄acyl.
 6. The compound according to claim 5 and wherein: Ar¹ is formula(A) or (B)

and R² is chosen from

when Ar¹ is formula (A) then: when R¹ is J-S(O)₂—N(R^(a))— orJ-N(R^(a))—S(O)₂— then J is C₁₋₃ alkyl; and when R¹ is NH₂,J-N(R^(a))—(CH₂)_(m)—, NH₂C(O)—, J-N(R^(a))—C(O)—, then J is C1–3 alkyloptionally substituted by R^(b).
 7. The compound according to claim 6and wherein: R^(b) is chosen from hydrogen, C1–5 alkyl, C3–6cycloalkylC0–2 alkyl, phenyl, C1–5 alkoxy, amino, C1–5 alkylamino, C1–3dialkylamino, C1–3 acyl, C1–5 alkoxycarbonyl, C1–3 acyloxy, C1–3acylamino, hydroxyl and halogen.
 8. The compound according to claim 7and wherein: R^(b) is chosen from amino, C1–5 alkylamino and C1–3dialkylamino.
 9. The compound according to claim 6 and wherein: Ar¹ isformula (A).
 10. The compound according to claim 6 and wherein: Ar¹ isformula (B).
 11. The compound according to claim 6 and wherein: Ar¹ is


12. A compound chosen from:1-Methyl-7-(2-methylcarbamoyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid[5-tert-butyl-3-(2-dimethylamino-ethylcarbamoyl)-2-methoxy-phenyl]-amide7-[2-(2-Dimethylamino-ethylcarbamoyl)-pyridin-4-yloxy]-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Dimethylamino-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-methylcarbamoyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Benzyloxymethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2-Hydroxymethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(2-piperazin-1-yl-pyrimidin-4-yloxy)-1H-indole-2-carboxylicacid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide7-(2,6-Dimethyl-pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide and7-(2-Ethyl-pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide1-Methyl-7-(pyridin-4-yloxy)-1H-indole-2-carboxylic acid(5-tert-butyl-3-{[(2-dimethylamino-ethyl)-methyl-amino]-methyl}-2-methoxy-phenyl)-amideor the pharmaceutically acceptable salts, acids or isomers thereof. 13.A compound chosen from:1-Methyl-7-(2-methylaminomethyl-pyridin-4-yloxy)-1H-indole-2-carboxylicacid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amideand7-(2-Dimethylaminomethyl-pyridin-4-yloxy)-1-methyl-1H-indole-2-carboxylicacid (3-methanesulfonylamino-2-methoxy-5-trifluoromethyl-phenyl)-amideor the pharmaceutically acceptable salts, acids or isomers thereof. 14.A pharmaceutical composition containing a pharmaceutically effectiveamount of a compound according to claim 1 and one or morepharmaceutically acceptable carriers and/or adjuvants.
 15. A method oftreating inflammation in a disease wherein the disease is selected fromosteoarthritis, atherosclerosis, contact dermatitis, bone resorptiondiseases, reperfusion injury, asthma, multiple sclerosis, Guillain-Barresyndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versushost disease, systemic lupus erythematosus, insulin-dependent diabetesmellitus, rheumatoid arthritis, toxic shock syndrome, Alzheimer'sdisease, diabetes, inflammatory bowel diseases, acute and chronic pain,stroke, myocardial infarction alone or following thrombolytic therapy,thermal injury, adult respiratory distress syndrome (ARDS), multipleorgan injury secondary to trauma, acute glomerulonephritis, dermatoseswith acute inflammatory components, acute purulent meningitis,necrotizing entrerocolitis, restenosis following percutaneoustransluminal coronary angioplasty, traumatic arthritis, sepsis andchronic obstructive pulmonary disease said method comprisingadministering to a patient a pharmaceutically effective amount of acompound according to claim
 1. 16. A process of making a compound of theformula (I):

Ar₁, X, Y, Q, W, R³, R⁴, R⁵,R⁶ and R^(y) are defined in claim 1; saidprocess comprising

coupling under suitable conditions an amine bearing Ar¹ carboxylic acidof the formula (III), where P is a protecting group, removing theprotecting group P to provide an intermediate of formula (V) undersuitable conditions; coupling under suitable conditions the intermediate(V) with a halo heterocycle VI (Z=halogen) bearing R⁶ in the presence ofa suitable base to provide a compound of the formula (I):